Evolution of Phototransduction, Vertebrate Photoreceptors and Retina.

Chapter III. Evolution of Vertebrate Photoreceptors

Trevor D Lamb

Chapter I: [1. Introduction] [2. Origins] [3. Ciliary photoreceptors in the eyes of extant chordates] [4. Gradations in chordate eyes: retina and photoreceptors]
Chapter II: [5. Pre-vertebrate chordate C-opsins] [6. Vertebrate 'visual' opsins]
Chapter III: [7. Vertebrate retinal cones and rods] [8. Evolution of the vertebrate retinal phototransduction cascade] [9. Cones: Photoreceptors with exceptional performance] [10. Noise: Thermal isomerization and other sources of noise] [11. Rod specializations and the origin of rods] [12. Retinoid re-isomerization in darkness]
Chapter IV: [13. Development of the retina at a macroscopic level] [14. Molecular signatures and cell differentiation in the vertebrate retina] [15. Synaptic transmission from photoreceptors to ganglion cells] [16. Retinal processing: Bipolar cells and the photopic and scotopic pathways]
Chapter V: [17. When did spatial (imaging) vision arise in the chordate lineage?] [18. Conclusions: Scenario for the evolution of photoreceptors and the vertebrate retina] [19. Summary] [20. References]

7. Vertebrate retinal cones and rods

The triumph of ciliary cells as the primary photoreceptors in vertebrates

In view of the fact that the image-forming eyes of most protostomes employ microvillar photoreceptors, it is natural to ask why vertebrate eyes instead opted for ciliary photoreceptors. Furthermore, given that a single type of fly rhabdomeric photoreceptor can reliably detect individual photons, and also respond very rapidly over an enormous range of intensities (reviewed in Yau & Hardie, 2009), it is also appropriate to ask why vertebrates instead use a duplex retina with separate cone and rod divisions.

In considering the relative merits of ciliary and microvillar photoreceptors, and the likely reasons why one or other of these classes triumphed in different organisms, it is important to avoid the error of simply comparing properties between the photoreceptors of living organisms. For example, it is not appropriate to argue on the basis of a comparison between the properties of modern rhabdomeric photoreceptors in flies and modern cone and rod photoreceptors. Instead, one needs to take into consideration the properties of the photoreceptors, and the circumstances of the organisms, at the relevant stage in evolution when the cell type gained its dominance; i.e. at the time when the 'choice' of photoreceptor class was made. At the stage when ciliary photoreceptors first became dominant in the retinas of chordates, more than 500 Mya, the evidence suggests that rods had not yet evolved. Likewise, at the stage when microvillar photoreceptors gained their dominance in protostome compound eyes, possibly more than 550 Mya, it is unlikely that they had yet become true rhabdomeric photoreceptors or that they had yet evolved the highly specialized (and possibly unique) kind of phototransduction cascade of Drosophila eyes (e.g. Hardie & Franze, 2012). Accordingly, one needs to investigate the relative merits of the rather simpler ciliary and microvillar photoreceptors that were likely to have existed in those ancient times.

With those points in mind, we can list a number of advantages that ciliary photoreceptors might have had over microvillar ones, at the time that the 'choice' between them was made:

E-1) Firstly, the polarity of response (hyperpolarizing to light and depolarizing to darkness) meant that ciliary photoreceptors would have been ideally suited for shadow detection in ancient organisms. The depolarization induced by a shadow could have triggered either an action potential or an increase in release of synaptic transmitter without additional logic, and this might have been advantageous for an animal with a simple nervous system.

E-2) Secondly, there may have been little difference in gain between the two classes of photoreceptor. Very recently, Ferrer et al (2012) have shown that the gain of transduction in amphioxus microvillar photoreceptors is much lower than the gain in modern rhabdomeric photoreceptors. However, the extremely short duration of the quantal response in chordate microvillar photoreceptors (a few ms; Gomez et al, 2009) may have been disadvantageous in comparison with the slower responses of ciliary photoreceptors.

E-3) Thirdly, it has been calculated that in a bright environment the energy consumption is lower for a hyperpolarizing ciliary photoreceptor, in which the ionic currents decrease in the light, than for a depolarizing microvillar photoreceptor, in which the ionic currents increase in the light; on the other hand the energy consumption of the two classes of photoreceptor is comparable in darkness (Okawa et al, 2008). A duplex retina has a further advantage in a bright environment because the rods saturate, thereby reducing their energy consumption to a low level, and it is only the cones that continue to generate a circulating current with its consequent energy demand (Fain et al, 2010).

E-4)Fourthly, chordate ciliary opsins (but not other ciliary opsins) underwent intra-molecular changes that substantially increased the efficacy of their activation of the G-protein. As a consequence, though, they lost the ability to undergo photoreversal.

E-5) Fifthly, these new ciliary opsins exhibited quite rapid decay of the active metarhodopsin II state, releasing bound all-trans retinal, and thereby enabling the binding of 11-cis retinal. Such release would have been made essential by the inability of the pigment to undergo photoreversal; however it is also possible that this change preceded the increase in activation efficacy. In the case of bistable opsins (R-opsins and the early C-opsins), the activated pigment remains in the metarhodopsin state for an extended period after exposure to light, so that the pool of rhodopsin available to detect incident photons is depleted. In this respect, a bistable photopigment may have been severely disadvantageous when an organism moved from a bright environment to a dim environment and needed to dark-adapt rapidly. Chordate ciliary photoreceptors may thus have provided a distinct advantage under such conditions.

E-6) Finally, an additional benefit to the organism may have arisen not directly from the properties of the phototransduction process, but from the fact that the ciliary cells evolved synaptic transmission onto their microvillar counterparts (see Section 15), thereby constituting a dual photoreceptive system via a single afferent pathway.

In any case, as the discussion above shows, it is possible to point to several important ways in which ciliary photoreceptors may have proved superior to microvillar photoreceptors in ancient chordates. For one reason or another, ciliary photoreceptors did indeed triumph in the light-sensitive organs of proto-vertebrates.

Multiple classes of vertebrate retinal photoreceptor

For a review of the distribution of opsins and the variations in morphology and in transduction pathways across classes of vertebrate photoreceptors, see Ebrey & Koutalos (2001).

As described in Section 6, the ancestral vertebrate possessed five classes of cone/rod opsin photopigment. In addition it possessed five morphological classes of cone/rod photoreceptor. On the basis of the norm in photoreceptors of jawed vertebrates, as well as circumstantial evidence from extant lampreys (Figue 15), it seems likely that each class of photoreceptor expressed a single class of opsin.

In jawed vertebrates, these photoreceptors comprise four classes of cone, expressing their individual cone opsins (SWS1, SWS2, Rh2, LWS), plus a single class of rod photoreceptor expressing the rod photopigment, rhodopsin (Rh1). However, at least in amphibia, the SWS2 'cone' opsin can additionally be expressed in another class of rods (called 'green rods' because of their greenish tint). In living lampreys, all five classes of photoreceptor appear cone-like, though the class that expresses 'rhodopsin' has some rod-like properties (Section 3). As a result, it is plausible that 'true' rods had not evolved prior to point #5 in Fig. 1. The timing of the emergence of rods will be discussed in Section 11.

Currently it is not clear whether the initial driving force for the multiplicity of spectral classes of cone photoreceptor was simply in order to cover more of the 'visible' spectrum, given that each opsin absorbs over a relatively narrow region of the spectrum, or whether it was to provide 'color vision'. But it seems reasonable to think that, almost as soon new spectral information became available to an organism, it would have been utilized by the nervous system to provide color information.

Morphological differences between cones and rods

Details of the morphology of cone and rod photoreceptors are given in Webvision Part I, Chapter 2 'Photoreceptors'; here we will simply concentrate on differences between the two classes of cell.

Sac versus disc structure. The most marked morphological difference between mammalian cones and rods relates to the topology of the outer segment membrane. In cones, the entire membrane is continuous with the plasma membrane of the inner segment, whereas in rods the bulk of the outer segment membrane is sealed off from the plasma membrane in the form of discs that resemble deflated balloons. These discs are not actually 'free floating', but appear to be tethered to the plasma membrane by proteins including peripherin/RDS, Rom1, and the GARP domain of the cyclic nucleotide-gated channel.

In both cell types, new outer segment membrane is continually being formed in the vicinity of the ciliary neck, and bulges outwards, so that new sacs are repeatedly formed beneath recently formed ones, in a mechanism that was documented experimentally by Steinberg, Fisher & Anderson (1980); see Fig. 16B above. They showed that a process of rim formation occurs between the membranes of adjacent sacs, though in cones it proceeds only part way around the circumference, so that the sacs are always open to the exterior (patent). In rods, however, this process of rim formation proceeds all the way around the circumference (bi-directionally), zippering together the apposed surfaces, and thereby forming a disc pinched-off from the plasma membrane.

As a result of this 'sealing over' of discs in rods, newly synthesized protein is trapped in the newly formed discs. As additional discs are created, those formed earlier slowly migrate outward along the length of the outer segment, over a period of weeks, before being phagocytosed by the RPE. This localization and migration of proteins can be demonstrated experimentally by autoradiographic examination at successive times after application of labeled amino acids (Young, 1976). In contrast, what is seen in cones is a uniform distribution of label over the entire outer segment, as expected if protein is able to diffuse (even very slowly) throughout the continuous plasma membrane of the outer segment.

Other morphological differences. A further morphological difference between their outer segments is the existence of one or more incisure(s) in rods; these deep longitudinal indentations into the outer segments provide an increased cross-section of cytoplasmic space that increases the effective longitudinal diffusion coefficient for intracellular messengers (see also Section 11). At the level of the inner segment, cones exhibit specializations that do not occur in rods, including the paraboloid and sometimes spectral filters (an oil droplet or vesicles, in the ellipsoid). Probably because of its high refractive index, the inner segment of cones is very effective in funneling incident light into the outer segment, and this gives rise to a marked Stiles-Crawford directional effect in cones, and a weak one in rods. At their synaptic terminals, cones and rods differ substantially, with the cones exhibiting large pedicles and the rods exhibiting smaller spherules. In addition, there are other subtle morphological differences between cones and rods.

Overview of functional differences between cones and rods

The light response properties of cone and rod photoreceptors are remarkably similar to each other (see below), and the cells exhibit just a few major differences:

(a) Rods. The defining feature in the response of the rod photoreceptor is its ability, under dark-adapted conditions, to respond reliably (i.e. with good signal-to-noise ratio) to the absorption of individual photons of light (Hecht, Shlaer & Pirenne, 1942; Baylor, Lamb & Yau, 1979). This single-photon detection performance is possible because the noise, expressed as 'dark light', is very low in rods; this dark light is many orders of magnitude lower in rods than in LWS cones, though the difference may be smaller in the case of SWS cones.

(b) Cones. The defining features in the responses of the cone photoreceptor are its ability: (i) to respond rapidly, (ii) to function over an enormous range of intensities, so that (iii) it never saturates in steady light, no matter how bright the intensity, and (iv) its ability to recover much of its responsiveness almost instantaneously when an intense light is extinguished (reviewed in Lamb, 2010).

Cone/rod similarities. In most other respects, the responses of cone and rod photoreceptors are remarkably similar to each other, as shown in Table 3 for human LWS cones compared with rods. For example, the amplification of the phototransduction cascade appears to be reasonably similar in mammalian cones and rods, and the observed difference in sensitivity between them (of around 20-fold) results in large part from the more rapid shut-off of the cone response, which is typically around 5-times faster than in rods under dark-adapted conditions. As illustrated in Fig. 24, cone and rod responses begin rising with broadly similar gain, but the cone responses recover much sooner. It has also been shown that the shapes of the light responses (i.e. their kinetics) are closely similar, apart from an overall scaling of the time axis.

Figure 24. Comparison of single-photon responses in LWS and SWS cones and a rod. Averaged responses to a single photoisomerization in representative dark-adapted photoreceptors of the salamander. The photopigments in these cells are: L cone, LWS; S cone, SWS2; rod, Rh1. The responses reach peak in approx. 200, 400 and 600 ms, and their amplitudes are roughly in the ratio 1 : 6 : 12. From Rieke & Baylor (2000).

However, the gain of transduction and the rate of activation of G-protein by activated opsin are probably not exactly equal in cones and rods, and indeed there are several reports of a lower gain in cones. Kawamura & Tachibanaki (2008) reviewed measurements from isolated cones and rods of fish and salamander, and concluded that the gain in the cones was considerably lower. More recently, Tachibanaki et al (2012) conducted careful experiments on the rate of G-protein activation by light-activated visual pigment, and found this rate to be ~5× lower in cones than in rods. Nevertheless, a recurring difficulty in measurements of cone biochemistry is that the shut-off reactions are so fast that this creates problems in determining activation rates. Overall, it seems likely that the gain of transduction in cones lies somewhere in the range 0.2-1× that in rods.

The responses in Fig. 24 also illustrate the general observation that cone photoreceptors expressing blue/green-sensitive opsins (i.e. those with the SWS1, SWS2, or Rh2 opsin) typically tend to display response properties intermediate between those of LWS cones and rods; thus, blue/green-sensitive cones are slower and more sensitive than red-sensitive cones.

Table 3. Comparison of light response properties of human LWS cones and rods. Parameter values are representative, and have been taken from numerous different sources. The parameters with very large cone versus rod differences are shown in bold red. Note that the turnover time for cGMP in cones is effectively much shorter than shown, even for the dim-flash response, because of the combination of the flash-induced activation of PDE within each sac and the calcium feedback loop.

Major cone/rod differences in performance. In Table 3 the parameters exhibiting major differences between cones and rods are indicated in red. Firstly, although cones and rods both exhibit classical Weber-law light adaptation, for rods this occurs only over a restricted range of intensities before they saturate, whereas for cones the adaptation continues up to indefinitely high intensities so that they never saturate in steady light. Secondly, rods typically display a very low rate of photon-like events in darkness, of the order of one event per tens or hundreds of seconds, whereas in LWS cones the 'dark light' may typically be of the order of hundreds of photon events per second. Although much of this difference in dark light stems from the difference in wavelength of peak absorbance (Section 10), a small part appears to be due to intrinsic differences between rhodopsin and cone opsins. Finally, following extinction of a steady light that bleaches more than 90% of the photopigment, human cones recovery their circulating current within ~20 ms (Kenkre et al, 2005), whereas for human rods comparable recovery of circulating current may take 20 mins, which is slower by a factor of ~60,000×.

These differences will be treated according to the photoreceptor class that exhibits the superior performance. Thus, the avoidance of saturation and the speed of response will be dealt with in Section 9 on cone photoreceptors, while transduction noise and the ability to resolve individual photons will be treated in Sections 10 and 11.

8. Evolution of the vertebrate retinal phototransduction cascade

Evolution of the vertebrate retinal phototransduction cascade

In this Section we will investigate the evolution of the 'vertebrate-style' phototransduction cascade that is employed in chordate ciliary photoreceptors, with emphasis on those of the vertebrate retina. The similar cascades utilized in protostome and cnidarian ciliary photoreceptors will be mentioned only in passing. The aims will be (1) to determine the nature of the phototransduction cascade that existed in a chordate ancestor of ours, just prior to the '2R' rounds of whole-genome duplication, and (2) to determine the manner in which that cascade became specialized in cones and rods. Thus, we will be examining the co-evolution of components of the cascade, initially in pre-vertebrate chordates, and thereafter in the earliest vertebrates.

Evolution of bilaterian phototransduction cascades

In Fig. 25A, the major components of several phototransduction cascades are contrasted, for vertebrate photoreceptors (top), for other ciliary photoreceptors, and for microvillar photoreceptors (Terakita et al, 2012). Each of these cascades appears to have evolved from a common ancestral form.

Figure 25. Co-evolution of components of phototransduction cascades. A, Components of the phototransduction cascades in ciliary and microvillar (rhabdomeric) photoreceptors. From Terakita et al (2012). B, Sequence of evolution for the components of phototransduction cascades proposed by Plachetzki et al (2010). Bottom left: The ancestral (non-photosensitive) G-protein cascade utilized a GPCR that coupled ultimately to a CNG (cyclic nucleotide-gated) channel. Third from left: The mechanism in the ancestral light-sensitive cell was similar. Top right: Early in the bilaterian lineage two variants of this scheme arose, both of which have been preserved in protostomes and deuterostomes. (Note that the obscured rear diagram for protostomes is the same as the front diagram for deuterostomes, and vice versa.) The ancestral mechanism was retained only slightly modified in the ciliary variety of photoreceptors, that expressed C-opsins. But the microvillar variety of photoreceptors, that expressed R-opsins, instead coupled via a Gq G-protein (and unknown intermediaries) to a TRP (transient receptor potential) channel. Additional abbreviations: I, intermediary molecules; Ic, ciliary intermediaries such as phosphodiesterase (PDE) and guanylyl cyclase (GC); Ir, rhabdomeric intermediaries such as phospholipase C (PLC), DAG (diacylglycerol) and PIP2 (phosphatidylinositol-4,5-biphosphate). From Plachetzki et al (2010).

Co-evolution of cascade components. The co-evolution of molecular components across phototransduction cascades was investigated by Arendt & Wittbrodt (2001), who compared the phylogenies of the genes for opsin, plus its G-protein, kinase, and arrestin, across protostomes and deuterostomes. They found clear evidence that all four of these components must have been present in the common bilaterian ancestor.

Coupling to G-proteins. The coupling of opsin type with G-protein type was examined by Koyanagi et al (2008) and has recently been reviewed by Terakita et al (2012). They categorized opsins into four groups according to the G-proteins to which they coupled. Chordate C-opsins couple to Gi/Gt; at least one cnidarian C-opsin couples to Gs; invertebrate 'Go-opsins' couple to Go; while all R-opsins couple to Gq.

Origin of cascades using CNGCs. The evolution of the coupling of opsin to via its G-protein to an ion channel was investigated by Plachetzki et al (2007, 2010). For the downstream effector mechanism, at the level of the cell's electrical response, Plachetzki et al (2010) provided evidence that the ancestral cascade had employed CNGCs (cyclic nucleotide-gated channels), as illustrated in Fig. 25B. Furthermore, the alternative TRP/TRPL (transient receptor potential-like) channel mechanism appeared to have arisen at a later stage, in microvillar photoreceptors, where the R-opsin couples via Gq.

Molecular components of the vertebrate phototransduction cascade

The molecular and cellular mechanisms underlying activation and recovery of the (modern) vertebrate phototransduction cascade are dealt with in detail in Webvision Part V, Chapter 1 'Phototransduction in Rods and Cones', as well as in numerous reviews, including Lamb & Pugh (2006a), Wensel (2008), Yau & Hardie (2009), etc. The principal proteins involved, both in cones and rods, are shown schematically in Fig. 26. For an overview of these proteins and their functions, see Wensel (2008); for a review of the proteins mediating shut-off of R*, see Gurevich et al (2011).

Figure 26. Molecular components of the vertebrate phototransduction cascade. The proteins underlying the activation phase of the phototransduction cascade in a cone are illustrated schematically; because the membrane configuration of a cone rather than a rod is illustrated, the ion channel and ion exchanger are in the same membrane as the other proteins. From Larhammar et al (2009). The names of the corresponding genes are listed nearby, with those for activation above and those for recovery and regulation below or to the right. Note, though, that icons for the RGS9/Gβ5/R9AP complex and the Na+/Ca2+,K+ exchanger (SLC24A1) are not included in this diagram. Where there is a clear distinction between expression in cones and rods, the genes are colored red for cones and blue for rods, while black indicates expression in both cones and rods; see Nordström et al (2004) for references. A more complete list of the proteins/genes involved in phototransduction, as well as those involved in the recycling of retinoid, is given in Table 4. Note that the arrestin gene SAG (retinal S-antigen) has a previous alias ARR1, and that ARR3 has previous alias ARRX. The ion channel is a tetramer, composed of both α and β subunits, and is permeable to monovalent and divalent cations. In cones, it comprises two CNGA3 and two CNGB3 subunits; in rods, it comprises three CNGA1 subunits and a single CNGB1.

Summary of molecular mechanisms. The molecular mechanisms of phototransduction are almost identical in cones and rods. Photoisomerization of a molecule of visual pigment to its active form R* triggers the catalytic activation of the G-protein (Gt, transducin) to G*, which in turn activates the cGMP phosphodiesterase (PDE6) to E*. The increased hydrolysis of cGMP lowers its cytoplasmic concentration, causing closure of cyclic nucleotide-gated channels (CNGCs). This suppresses the circulating electrical current that had been flowing in darkness, hyperpolarizing the cell; in addition, it leads to lowered cytoplasmic Ca2+ concentration through the continued activity of a Na+/Ca2+,K+ exchanger, and this drop in Ca2+ level is important for response recovery. Response shut-off requires inactivation of each of the activated forms, as well as restoration of cGMP levels. R* is rapidly inactivated by the binding of arrestin, but this step first requires the R* to have been phosphorylated by a G-protein receptor kinase (GRK). The G*/E* complex is rapidly inactivated by hydrolysis of the terminal phosphate of the GTP bound to G*, through the action of the GTPase accelerating (GAP) activity of the RGS9-Gβ5-R9AP complex. The drop in Ca2+ concentration permits Mg2+ to bind to guanylyl cyclase activating proteins (GCAPs), thereby activating guanylyl cyclase (GC), restoring cGMP levels, and hence causing the re-opening of ion channels. This action of Ca2+ endows the photoreceptor with a powerful negative feedback loop that helps stabilize the electrical current.

Differences in isoforms and activities between cone and rod proteins

The proteins mediating the light response in cones and rods are closely similar; indeed a few of the proteins are identical in the two classes of photoreceptor, though in most cases distinct but closely related isoforms are expressed, as indicated by the gene names shown in Fig. 26 and listed in Table 4. A number of online resources exist for examining the genes involved in the eye, and two useful resources are RetinaCentral.org (with the 'retinome', or transcriptome of the retina/RPE; Schulz et al, 2004) and RetNet, sph.uth.edu/retnet (with retinal disease genes).

Table 4. Genes for proteins with known function in phototransduction or retinoid cycling. List of proteins with known functions in activation and recovery of the phototransduction cascade, and in the RPE retinoid cycle. Names of the human genes are given in column 2. Where there is a clear distinction between expression in cones and rods, the genes are colored red for cones and blue for rods, while black (and 'Both') indicates expression in both cones and rods, as in Figs. 26 and 27. Not enough is known about the intra-retina retinoid cycle in order to list its components. Many additional proteins have important functions in cones, rods, and RPE cells, apart from involvement in phototransduction and retinoid cycling, but are not listed here. Likewise, numerous other proteins are involved in signal transmission and neural processing within the retina

For several of the phototransduction proteins, the expression levels in cones are much higher than in rods, and this probably accounts for several instances of more rapid shut-off of the light-activated molecules. A notable example is the 10-fold higher expression level in cones of the molecular complex RGS9/Gβ5/R9AP that shuts off the activated G-protein, transducin, when it is bound to the PDE. For shutting off activated rhodopsin, cones and rods in many species employ different isoforms of the GRK (G-protein receptor kinase): in cones it is typically GRK7 whereas in rods it is GRK1; in this case, the difference in isoform probably contributes substantially to differences in lifetime of activated rhodopsin and therefore in sensitivity of the response (Kawamura & Tachibanaki, 2008; Vogalis et al, 2010; Korenbrot, 2012).

The overall effects of the differences in activities and expression levels of the different isoforms of phototransduction proteins have been analyzed and modeled by Kawamura & Tachibanaki (2008) and Korenbrot (2012), who have been able to account well for the observed differences in kinetics and sensitivity between cones and rods.

Evolution of components of the vertebrate phototransduction cascade

For vertebrate phototransduction, Hisatomi & Tokunaga (2002) compared the phylogenies of the genes for eight families of the proteins involved (transducin, PDE, CNGC, GRK, arrestin, recoverin, GC, GCAP). They noted close similarity in the branching patterns of the gene dendrograms, and concluded that each of these families appeared to have evolved 'cone' and 'rod' branches, though in two cases (PDE and GCAP) there had been a further duplication in the rod branch. More recent results, examining the evolution of individual components of the phototransduction cascade, will now be presented.

Transducin. The origin of transducin alpha subunits was investigated by Muradov et al (2008), who identified two isoforms in lamprey, that they named GαL and GαS, for their expression in the long (cone-like) and short (rod-like) photoreceptors, respectively. GαL is roughly equally distantly related to cone and rod transducin alpha subunits of jawed vertebrates, and might represent the ancestral form, whereas GαS clades with the rod version, though it retains certain cone-like characteristics such as the presence of the 'hallmark' four-residue sequence near the N-terminus. In order to determine the timing of the duplication that gave rise to these two transducin alpha subunits, there is additional information that can be obtained from analysis of the location of genes on chromosomes (see Section 8).

Phosphodiesterase. The phosphodiesterase (PDE6) used in vertebrate phototransduction is unique in its ability to be regulated by the gamma subunit (Pγ), and the co-evolution of these two components has been investigated by Muradov et al (2007) and Zhang & Artemyev (2010). Muradov et al (2007) cloned both components from lamprey. For the PDE6 catalytic unit, they found that lamprey has a single isoform (as in cones), with high homology to jawed vertebrate PDE6 catalytic units, though equally distantly related to those of cones and rods, and their results were consistent with the notion that PDE6 arose from a common PDE5/6/11 ancestor in the chordate lineage. They identified a tunicate PDE that grouped with vertebrate PDE6, but they could find no other non-vertebrate sequences grouping with PDE6.

For the regulatory Pγ subunits, they found two isoforms, one cone-like and the other intermediate between cone and rod sequences; no sign of similar sequences was found in tunicate databases. Their evidence suggested that these regulatory subunits arose in the stem vertebrate lineage, and that the common ancestor of lampreys and jawed vertebrates was likely to have already possessed two isoforms. This analysis was extended by Zhang & Artemyev (2010) who provided evidence that, although Pγ is a strictly vertebrate invention, the capacity of the PDE catalytic units to bind Pγ predated the emergence of the inhibitory subunit; indeed their analysis predicted that the PDE5/6-like enzymes of cnidaria should interact with vertebrate Pγ.

CNGCs. In cones the cyclic nucleotide-gated channel comprises two α subunits (CNGA3) and two β subunits (CNGB3), configured as A3-A3-B3-B3 (Peng et al, 2004), whereas in rods the channel comprises three α subunits (CNGA1) and a single β subunit (CNGB1). Nordström et al (2004) found strong evidence that the duplication that gave rise to the α and β subunits of the cyclic nucleotide-gated channel took place prior to the divergence of protostomes and deuterostomes, and they also found suggestive evidence that the multiple versions of α and β subunits may have arisen in the '2R' duplications.

GRKs. Mushegian et al (2012) have recently investigated the origin and evolution of G-protein receptor kinases (GRKs). They found evidence that GRKs originated prior to metazoa, through the insertion of a kinase (similar to a ribosomal protein S6 kinase) into a loop in a domain with homology to RGS (regulator of G-protein signaling). During chordate evolution an ancestral GRKa split into the GRK1/7 and GRK4/5/6 lineages. Mushegian et al (2012) suggest that this coincided with the first round of '2R' whole-genome duplication, though it is possible that the split may have occurred earlier, as an apparently ancestral GRK1/7 is present in the tunicate Ciona intestinalis. The results of Larhammar et al (2009) (see next Section) suggest that the distinction between GRK1 and GRK7 arose during the '2R' duplications. However, further work is needed to resolve the origin of these isoforms.

Arrestin. The phylogeny of arrestins (including 'visual' arrestin) has been studied by Gurevich & Gurevich (2006) and Alvarez (2008), and the function of these proteins has been comprehensively reviewed by Gurevich et al (2011). Arrestins arose very early in metazoan evolution, with the family comprising both the β-arrestins (named after their interaction with the β-adrenergic receptor) and the 'visual' arrestins having diverged from a much larger family in pre-bilaterian times (see Alvarez, 2008). A clue to the nature of the much more recent split between vertebrate visual arrestins and β-arrestins has been provided by Kawano-Yamashita et al (2011) who reported that the pineal non-bleaching opsin, parapinopsin, appeared to be inactivated by a β-arrestin through a process of internalization (as in other β-arrestins). They noted that Ciona intestinalis photoreceptors apparently use a β-arrestin, and they proposed that the vertebrate-style visual arrestin had evolved specifically for use in shutting-off opsins that release their retinoid; i.e. specifically in the case of vertebrate visual opsins.

Chromosomal arrangement of phototransduction genes

The paralogon arrangement of the opsin genes was presented in Section 6. Here we consider the results of Larhammar et al (2009) relating to the paralogon arrangement of other components of phototransduction.

Transducin alpha subunits. Interestingly, Larhammar et al (2009) showed that the gene for the transducin alpha subunits was in the same paralogon as the opsins, and close by (see Fig. 23). Recently, Lagman et al (2012) have combined an analysis of the gene arrangements for each of the three subunits of the trimeric transducins with sequence-based analyses, and they have provided evidence that all three families of transducin subunit expanded during the early vertebrate tetraploidizations. They concluded that the early vertebrate tetraploidizations provided the basis for the subsequent specialization of transducin subunits leading to differential expression between cones and rods.

The original GNAT gene may have arisen by duplication within the deuterostome lineage of the ancestral GNAI/GNAT gene present in bilaterians, as some protostomes have homologs of GNAI, but none have homologs of GNAT; alternatively, the duplication could have occurred earlier, but with GNAT being lost in protostomes.

Other components of the phototransduction cascade. Larhammar et al (2009) also found apparent remnants of a paralogon arrangement in a local grouping of the genes for the transducin beta subunits, for the GRKs, and for the arrestins (their Fig. 5). In addition they found evidence for '2R' expansion of the genes for PDE6, and for both the alpha and beta subunits of the CNGC channel, as well as for arrestin and the GRKs.

Interpretation. For many of the proteins involved in the phototransduction cascade, there is a difference (either partial or complete) in the distribution of isoforms between cones and rods, and for at least 10 of the 13 protein components studied by Larhammar et al (2009) the differentially-distributed isoforms arose as a result of the '2R' duplications at the base of the vertebrate lineage. Accordingly, there seems little doubt that much of the distinction between the cone and rod transduction cascades can be traced to the reduction in constraints on gene mutation that resulted from the two whole-genome duplications.

Hypothesized nature of pre-vertebrate ciliary photoreceptor and transduction cascade

From the available evidence, it does not yet seem feasible to paint a scenario for the detailed sequence of events that transformed an ancestral bilaterian photoreceptor into a vertebrate photoreceptor. However, it is possible to propose the following for the state that had been reached, in the evolution of the 'proto-cone' photoreceptor and its phototransduction cascade, just prior to the '2R' whole-genome duplications that occurred near the base of the vertebrate lineage:

F-1) The ancestral cone opsin of the 'proto-cone' photoreceptor was broadly similar to modern SWS and LWS cone opsins, and in particular it had evolved a high efficacy of activation of the G-protein.

F-2) Duplication of that ancestral cone opsin created a pair of retinal cone opsins: an SWS opsin with the standard E181 residue, and an LWS opsin with the H181/K184 combination that provided a chloride-binding site giving a substantially red-shifted absorption. The SWS and LWS opsins were expressed in separate, but closely similar, cones. The output signals from those cones could potentially have been utilized to provide dichromatic color vision.

F-3) The primary additional proteins involved in activation of the cascade had evolved to become: (i) the ancestral transducin Gt, with unique alpha, beta and gamma subunits; (ii) the ancestral PDE6 cyclic GMP phosphodiesterase, comprising a pair of identical catalytic subunits and a pair of identical regulatory (gamma) subunits; and (iii) a tetrameric cyclic nucleotide-gated channel composed of two classes of subunit, alpha and beta.

F-4) The Gαt had probably arisen from a common ancestral Gαi / Gαt during chordate evolution. The PDE6 had arisen from a common ancestral PDE5/6/11 during chordate evolution. The PDE regulatory subunit had arisen late in chordate evolution, after the divergence of tunicates (i.e. after #4 in Fig. 1).

F-5) The primary proteins involved in response recovery and regulation had evolved to become the ancestral 'cone' components, specified by the genes GRK7, ARR3, RGS9, GUCY2D/F, GUCA2, SLC24A1 and RCV1, in addition to the cone opsins themselves.

F-6) The presence of all these components suggests that response shut-off occurred in a manner fundamentally similar to that in modern vertebrate photoreceptors.

F-7) In particular, the co-existence of the components required for the Ca2+ feedback loop (GUCA2, GUCY2D/F, CNGC) provides strong circumstantial evidence that the negative-feedback loop that stabilizes the circulating current, and assists in light adaptation, was already present.

F-8) All the components of the transduction cascade were expressed in the membranes of the lamellar sacs that radiated laterally from the cilium of the proto-cone.

F-9) Because of the release of all-trans retinoid from activated opsin, the photoreceptor's outer segment required a source of 11-cis retinoid, and this may have been provided by the glial (Müller) cells.

F-10) The cell had evolved a simple glutamatergic synapse, permitting synaptic transmission.

9. Cones: Photoreceptors with exceptional performance

Cones exhibit high sensitivity, high speed, and high contrast sensitivity

High sensitivity. Despite frequent claims to the contrary, cone photoreceptors are highly sensitive, and the amplification of transduction appears to be quite similar to that of rods. Indeed, when one views a dim star at night, it is the cones (and the photopic system) that detect the star. For example, in viewing the Pleiades (Seven Sisters), although one will be aware of the cluster as a blur in the parafoveal field by means of scotopic vision, when one fixates the individual stars then it is the cones that are detecting them. The rod system is much better for the diffuse cluster, because of its wide spatial summation, but the cone system is better at detecting individual stars, because of its higher spatial resolution. The sensitivity of individual cones is sufficient to detect quite dim stars, though for very dim stars one may be better off using parafoveal rod vision.

High-speed response. The speed of response in cone photoreceptors is far higher than in rods, and this speed increases with increasing background intensity. In bright illumination, the human photopic visual system is able to resolve sinusoidal or square-wave flicker at frequencies of around 100 Hz (Tyler & Hamer, 1990), for which the brighter/dimmer periods are ~5 ms each. Thus, it seems that light-adapted cones are able to generate a resolvable signal when the illumination is extinguished for as short a duration as about 5 ms.

High contrast sensitivity. The human photopic (cone) system is able to detect very small fractional changes in intensity. Thus, under light-adapted conditions, an observer can detect a contrast of 0.5%; for comparison the contrast sensitivity of the scotopic (rod) system is at least an order of magnitude poorer, at >5%.

Hence, the cone system is extremely sensitive, extremely fast, and it has excellent contrast sensitivity.

Avoidance of saturation by cones: Unlimited upper operating intensity

In contrast to rod photoreceptors, which saturate at quite low intensities, cone photoreceptors are remarkable for their ability to function well during steady illumination - no matter how intense that steady background is made (Normann & Werblin, 1974; Burkhardt, 1994). Although cones may saturate transiently at the onset of intense illumination, they rapidly recover and are able to signal increments and decrements, even when the illumination is so bright that it bleaches a large proportion of the photopigment. To account for this, Lamb & Pugh (2006b) compared the shut-off reactions in human cones and rods; they showed that the ability of the cones to avoid saturation can be explained in terms of the combination of the ~20-fold faster shut-off of the activated cone photopigment, and the ~20-fold faster shut-off of the activated cone Gt/PDE complex.

In human rod photoreceptors in vivo, the circulating current is halved at a steady intensity of ~70 scotopic trolands (600 R* s-1), with complete saturation occurring at ~1000 scotopic trolands (~104 R* s-1). If the activation gain of transduction is comparable in human cones and rods, then the two very short cone time constants would elevate the intensities required for half and full saturation by some ~400×, to levels of ~240,000 and ~4 × 106 R* s-1 in cones. Two additional factors are that the gain of transduction may be slightly lower in cones, and that the cGMP-gated channels of mammalian cones (in contrast to those of rods) show increased affinity for cGMP when Ca2+ falls; these factors would further increase the R* rate required to saturate the cone. Now, the highest steady rate of photoisomerization that can ever be reached in a human cone, by exposure to steady light, corresponds to the maximal rate of pigment regeneration, which has been shown by Mahroo & Lamb (2004) to be 0.75%/s, which in a cone containing 40 million molecules of cone opsin corresponding to ~300,000 R* s-1. Hence, this maximum possible rate of steady photoisomerizations is lower than the isomerization rate calculated above to be needed to saturate the cone, meaning that the cone can never be saturated by steady light.

A more intuitive way of understanding this is to say that very high steady intensities cause the cone opsin to bleach to a level low enough to prevent saturation of the response by the steady light. As a result, the photopic visual system is able to function over (i.e. to adapt to) an enormous range of intensities, from moon-lit conditions to the brightest sun-lit scenes.

Extremely rapid recovery of cone circulating current

When the human eye is exposed to steady light sufficiently intense to bleach 90% of the photopigment in the rods, full recovery of the rod circulating current takes around 20 mins after extinction of the light (Thomas & Lamb, 1999). In contrast, a steady light that bleaches 90% of the LWS/MWS cone photopigment does not saturate the cone response (see above), and around half the circulating current remains. Upon extinction of that light, the cone circulating current recovers fully within ~20 ms, around 60,000-fold faster than for the rod (Kenkre et al, 2005).

As in the case of the cone's avoidance of saturation, the molecular mechanisms that enable this extremely rapid recovery of circulating current lie in the rapidity of the inactivation steps. Kenkre et al (2005) estimated that in the presence of bright light the time constants for the shut-off reactions were as follows: for R*, ~5 ms; for G*/E*, ~13 ms; and for cGMP turnover, ~4 ms. Using these parameters in a simple model of cGMP kinetics and channel activation, they were able to accurately fit their experimental measurements of the time-course of recovery of cone current. In rods, the extremely slow recovery of current is caused not by the slowness of inactivation/shut-off steps in the G-protein cascade, but instead by the slowness of the regeneration of visual pigment, combined with the fact that unregenerated opsin activates the cascade; for a full account of this slow recovery, see Lamb & Pugh (2004).

Morphological features required by a cone

The operational requirements of cone photoreceptors place certain constraints on the morphological features of the cells.

High surface to volume ratio of outer segment. In order to achieve rapid response kinetics, all the recovery reactions must be fast, including the Ca2+-mediated acceleration of guanylyl cyclase activity that permits rapid re-opening of the cyclic nucleotide-gated ion channels. This means that the time constant for equilibration of cytoplasmic Ca2+ concentration (τCa) must be short. In mammalian (including human) cones, τCa has been estimated as ~3 ms (van Hateren, 2005; van Hateren & Lamb, 2006), in contrast to its value in amphibian rods of the order of 400 ms or more. Simulations showed that if τCa was not kept as short as the longest of the other shut-off time constants, then the responses became strongly biphasic or even oscillatory.

Straightforward analysis shows that τCa should be inversely proportional to the activity of the Na+/Ca2+,K+ exchanger, but directly proportional to cytoplasmic volume (see eqn (15) of Lagnado et al, 1992). Accordingly, a high surface-to-volume ratio for the outer segment, that allows a large number of molecules of exchanger per unit volume of cytoplasm, will provide a short time constant τCa for Ca2+ and will therefore be advantageous for cones. In addition, the calcium buffering power of the outer segment will need to be kept low for cones.

Function of open sacs. The above requirement for a high surface-to-volume ratio no doubt provided a powerful driving force for the opsin-containing membrane of cones to remain in contact with the extracellular medium, and hence for the outer segment membrane not to seal over in the way it does in rods. In LWS cones, an additional driving force for the retention of open sacs may relate to the chloride-binding site, H197 (=H181 in the bovine rhodopsin frame), that confers a substantial red-shift in spectral sensitivity. This site is in the second extracellular loop, and in order to provide a high (and stable) chloride ion concentration on this side of the membrane, it is probably necessary for this region to remain extracellular, instead of transforming to become intradiscal as occurs in the discs of rods.

The existence of the sac structure in cone photoreceptors would appear likely to restrict both the membrane-based reactions and the cytoplasmic reactions resulting from a single photoisomerization to the domain of just a single sac; this could conceivably be either advantageous or disadvantageous, depending on the response property under consideration.

Synaptic release constraints. In order for cone photoreceptors to be able to transmit their graded (i.e. analog) signals rapidly, it is essential that the rate of release of synaptic vesicles be extremely high. This is necessary because the post-synaptic signal needs to be detected above the noise that is intrinsic to the quantal release of neurotransmitter vesicles. In order to be able to detect a change of (say) 1% in the release of vesicles, it is necessary that the mean number of vesicles released should be of the order of 1/(0.01)2, or 10,000. And in order for this to be achievable in (say) 100 ms, the rate of vesicle release would need to be around 100,000 vesicle s-1 which is enormously high. Accordingly, the cone's synaptic terminal requires a very large area for the active release zone, in order to achieve this kind of rate of vesicle release. For comparison, in a rod the response to a single photoisomerization is considerably larger than the cell's baseline noise, so that it may be adequate to be able to detect a change of the order of (say) 10%; in addition the rod's response is a much slower response than the cone's. Hence, a far lower rate of vesicle release (and hence a smaller synapse) would suffice to provide a sufficiently reliable post-synaptic signal from a rod.

Scenario for the refinement of vertebrate phototransduction in cones

The following scenario is proposed for the refinement of the phototransduction cascade in chordate ciliary photoreceptors, that occurred during the early evolution of the vertebrate retina:

G-1) By the time that the chordate lateral retinas began signaling spatial (i.e. visual) information (see Section 17) there was great evolutionary pressure for rapid responses, for high sensitivity, for the ability to adapt to different intensities, and for high contrast sensitivity.

G-2) Those pressures led to acceleration of each of the recovery steps in the cascade; i.e.: shut-off of activated opsin, shut-off of G-protein/PDE, turnover time for Ca2+ concentration, and Ca2+ feedback to the re-opening of ion channels.

G-3) To compensate for the reduced sensitivity that would inevitably have accompanied the faster responses, there would have been a continuation of the pressure for increased efficacy of activation of the G-protein by the activated opsin.

G-4) Given the existence of multiple classes of cone, not all of these needed to be equally fast or equally sensitive. The systems with shorter wavelength (and hence more thermally stable) opsins could afford to become slower, in order to achieve higher sensitivity. The LWS system, with its high intrinsic noise, was better suited to achieving the fastest performance.

G-5) In response to the intense pressure to be able to transmit responses rapidly, and also to be able to signal small changes in light level (low contrasts), changes took place in the synaptic terminal that led to very high rates of release of synaptic transmitter. In this way, even brief and small changes in cone intracellular voltage led to changes in post-synaptic transmitter concentration that could be detected above the noise inherent in the vesicular nature of release.

G-6) By the time that the first (jawless) vertebrates evolved, their lateral retinas possessed five spectral classes of cone photoreceptor that exhibited exceptional responses properties, broadly similar to those of modern vertebrate cones.

10. Noise: Thermal isomerization and other sources of noise

This Section examines sources of noise (fluctuations) in the responses of photoreceptors, beginning with intrinsic properties of the opsins and then within the transduction cascade.

Thermal isomerization of cone opsins and rhodopsins

In considering the differences between cones and rods, one major disparity relates to the level of noise: LWS cones are many orders of magnitude noisier than rods (Table 3). Here we will examine the extent to which this difference in noise is a function of the stability of opsin molecules with different peak wavelengths.

More than 60 years ago, Stiles (1948) developed a model describing the long-wavelength decline in spectral sensitivity of visual pigments, later expanded by Lewis (1955), invoking the concept that the thermal energy of vibration in the molecule could add to the energy of a photon in order to trigger activation. Barlow (1957) extended this concept, with the proposal that spontaneous thermal activation could occur, at a very low rate, even in the absence of light, and he predicted reduced stability (greater noise) for pigments of longer wavelength. Barlow's prediction has been borne out in numerous experimental studies (e.g. Ala-Laurila et al, 2004b; Luo et al, 2011), and theoretical models of varying complexity have been proposed to account for the exact relationship between peak wavelength and rate of thermal activation (e.g. Lewis (1955); Ala-Laurila, 2004a; Luo et al, 2011; Gozem et al, 2012).

One important observation is that 'cone' opsins can be incredibly stable, and this is most obvious when that particular opsin is expressed in a rod. In amphibia, the so-called 'green rods' (that absorb in the blue, and hence appear green) express a blue-sensitive pigment, which has been shown to be the SWS2 opsin that is also expressed in blue-sensitive cones in the same retina (Ma et al, 2001). Early electrophysiological experiments showed that green rods of the toad exhibit a very low rate of spontaneous thermal isomerizations (Matthews, 1984), and more recent experiments have shown this rate to be amazingly low, at <10-14 s-1 at 23 °C (Luo et al, 2011). This means that the SWS2 (cone) pigment, when expressed naturally in a toad rod, only activates spontaneously on average once every ~1014 s, or ~4000 years. Thus, this 'cone' pigment is the most stable of all known opsins, including conventional rhodopsins!

Cones: Dark noise

Intracellular voltage recordings from LWS cones in turtle have shown very high levels of noise (Lamb & Simon, 1977). Usually, this noise is reduced in amplitude by the 'averaging out' that results from the extensive lateral spread of signals across the electrically coupled network that is created by the gap junctions that link neighboring cones (Lamb & Simon, 1976). But in a cone that is not coupled to its neighbors (an 'electrically isolated' cone), the observed amplitude of dark noise, of around 3000 µV peak-to-peak, is truly enormous when compared with the mean single-photon response amplitude of only 25 µV, and utterly precludes the resolution of individual photon events. Calculations indicate that this dark noise is equivalent to the quantal fluctuations that would be produced by a real light of a little over 2000 photoisomerizations s-1; this parameter is termed the 'dark light' experienced by the cone. Experiments with backgrounds showed that application of a real light of this intensity roughly halved the flash sensitivity of the cone. Subsequently, in intracellular measurements from macaque LWS/MWS cones, Schneeweis & Schnapf (1999) found dark noise that they calculated to be equivalent to >3000 R* s-1per cone.

The source of these dark fluctuations in the intracellular voltage of LWS cones has not been established. In turtle cones, a significant contribution would be expected to come from thermal activation of the opsin (see above), because the wavelength of peak absorption is exceptionally long, at around 620 nm; indeed this appears to be the longest known wavelength of peak sensitivity of any opsin. If all the dark noise originated from thermal isomerizations, then the cone's opsin content of ~108 molecules divided by the event rate of 2000 s-1 would yield a mean thermal lifetime of 0.5 × 105 s, which is not far from the prediction of Luo et al (2011; their Fig. 4C) for a cone opsin of this wavelength. In addition to photopigment noise, the transduction process is also expected to contribute noise (see below). And finally, the chattering activity of ion channels in the synaptic terminal should contribute additional noise. To date, the relative contribution of these potential sources has not been evaluated. One way to investigate the contributions would be to use suction pipette experiments, though a potential drawback is that separation of the cone outer segment from its normal enmeshment amongst the processes of the RPE cells might conceivably alter the cone's performance compared with that in the intact retina.

Rods: Transduction noise and variability of the single-photon response

Transduction noise in rods. In rods, it is possible to separate noise in the transduction process (and subsequently) from the noise caused by thermal isomerization of rhodopsin, because of the fact that the spontaneous photon-like events are individually resolvable (at least, under dark-adapted conditions). In dark-adapted toad rods, Baylor et al (1980) reported that the residual 'continuous' noise corresponded to shot events with an amplitude around 1/400 of the single-photon event and occurring randomly at a mean rate of around 6000 events s-1. In functional terms, this source of noise can be considered low, simply on the basis that the great majority of single-photon responses are resolvable despite its presence.

Variability of the rod single-photon response. Despite the contrary view that is painted in most publications on the subject, the single-photon response of rods is quite variable, especially in terms of its time-course, yet most authors describe the kinetics as 'reproducible'. For toad rods, Whitlock & Lamb (1999) illustrated the wide variability in time-course of the single-photon response visually, by matching individual responses that began rising with a similar slope, and showing how different the peaks and falling phases could be. When they estimated the variation in a single shut-off step that was needed to account for the experimental measurements, they found a coefficient of variation (standard deviation divided by mean) of ~0.4. This is sufficiently high that it is not reasonable to describe the quantal responses as exhibiting 'reproducible' kinetics. The substantial variability in time-course, and also in amplitude, is a perfectly normal (and expected) feature of the known shut-off steps in the rod photoresponse, and has been accurately modeled by Hamer et al (2003, 2005) and Gross et al (2012).

Magnitude of the rod single-photon response. It has recently been shown that mouse rods in the retinal slice preparation exhibit considerably larger single-photon responses than reported previously using the suction pipette approach, with mean amplitudes of 2-3 mV in cells with ~20 mV maximal responses (Cangiano et al, 2012). With a single-photon response as large as this, reliable synaptic transmission of that response to rod bipolar cells is far less problematic than has frequently been suggested in the literature.

11. Rod specializations and the origin of rods

As discussed in Secction 7, the defining feature that distinguishes a rod photoreceptor from a cone photoreceptors is its ability, under dark-adapted conditions, to respond reliably (i.e. with good signal-to-noise ratio) to the absorption of individual photons of light (Hecht, Shlaer & Pirenne, 1942; Baylor, Lamb & Yau, 1979). Although numerous differences between cones and rods have been catalogued, in terms of morphology, molecular components, and response properties, there has never been a compelling account of what it is that enables vertebrate rods to achieve their photon-resolving performance.

This Section first analyzes structural features that contribute to the ability of rods to reliably signal individual photoisomerizations. It then examines two unusual types of 'rod': those of the nocturnal gecko, where the photoreceptors exhibit rod-like properties, yet are relatively recently descended from cones; and those in the all-rod retina of the skate, where the rods exhibit certain cone-like properties. Thereafter the emergence of rods in early vertebrates is considered, and finally a scenario is painted for the evolution of rod photoreceptors.

Structure as a factor in the rod's ability to signal individual photoisomerizations

In order to achieve a single-photon response amplitude of reasonable amplitude (say 5% of the circulating dark current), ion channels must be affected over a moderate length of the outer segment, and this necessitates longitudinal spread of the cytoplasmic messenger cGMP along the outer segment. The situation in a typical cone, where the cytoplasmic message is restricted primarily to the interior of a single sac during the short duration of the cone response, cannot provide a single-photon signal of more than 1/N of the circulating current, where N is the number of sacs in the outer segment (typically >500).

More effective longitudinal spread (a higher longitudinal diffusion coefficient) can be achieved by increasing the cross-sectional area available for longitudinal diffusion, as was originally modeled by Lamb et al (1981). In a cone outer segment, only a tiny proportion of the circumference of the sac is available as an intracellular route for longitudinal communication, and hence the effective longitudinal diffusion coefficient is low. But, by enclosing the sac membranes within the plasma membrane, through the formation of pinched-off discs, then essentially the entire circumference is available as a longitudinal conduit. The longitudinal diffusion coefficient can be further increased by the use of one or more incisures (longitudinal infoldings of the outer segment membrane), as this will increase the total length of the gap that encircles the discs, and hence will increase the cross-sectional area of the cytoplasmic path along the outer segment.

In the large rods of toads, Lamb et al (1981) measured the longitudinal spread of activation to have a length constant of the order of 3 µm at the time of the peak of the single-photon response, and they measured the steady-state spread of desensitization during light adaptation to have a length constant of around 6 µm. Subsequent studies have confirmed and extended these observations to mammalian rods.

With this extent of longitudinal spread of cytoplasmic messenger in the outer segment, the rod is readily able to achieve an amplitude for the single-photon response of 5% of the circulating dark current. The effect of such longitudinal diffusion on the time-course of the single-photon response was modeled by Lamb & Pugh (1992; their Appendix B).

Nocturnal gecko: Cones exhibiting rod-like properties

The photoreceptors of nocturnal species of gecko provide an important test of what is needed to make a 'rod', because in essence they are cones with a few rod-like features, yet they exhibit rod-like response properties. Walls (1934, 1942) proposed that the photoreceptors of nocturnal geckos had been 'transmuted' from cones into rods. He suggested that extant geckos were derived from a diurnal ancestor that had possessed an all-cone retina (i.e. one from which the rods had been completely lost). He suggested that nocturnal species of gecko had adapted by evolving rod-like outer segments, while retaining other morphological features of cones together with the organization of an all-cone retina. In more recent literature, most authors have referred to the retina of the nocturnal gecko (e.g. Gekko gekko) as being 'all-rod', and the photoreceptors as being 'rods', but this is not the case (see below).

Light responses. Intracellular recordings of light responses were made from photoreceptors of Gekko gekko by Kleinschmidt & Dowling (1978), who reported response properties broadly similar to those found in the rods of other species. The responses to dim flashes had a slow time-to-peak, of around 700 ms at 25 °C. Although those responses appeared very sensitive (and hence rod-like), I have not been able to extract a quantitative value for their sensitivity. The family of responses to flashes of increasing intensity is reminiscent of rod families. The response to a bright flash had an amplitude of ~20 mV, and exhibited a rapid sag from a peak to a plateau; this sag was eliminated by treatment with 100 mM aspartate, suggesting that it arose through feedback from horizontal cells; if so this aspect would be cone-like rather than rod-like, because rods typically display a rapid sag originating in the inner segment. In the presence of steady backgrounds, the photoreceptor's response light-adapted, over a range of ~4 log10 units, before saturating; such behavior is rod-like.

Rispoli et al (1993) reported voltage-clamp electrical recordings from isolated outer segments of Gekko gekko photoreceptors, that had been detached at the connecting cilium and then dialyzed with an energy-rich intracellular solution. The mean dark current was ~67 pA, and the family of responses to flashes of increasing intensity was remarkably similar to that seen in rods of other species. Responses to dim flashes had a time-to-peak of ~1.1 s at 17 °C, with kinetics of the form reported for rods. The dark-adapted flash sensitivity was calculated (from intensity measurements) to correspond to a single-photon response amplitude of ~0.8 pA, while fluctuation analysis (ensemble variance divided by mean) gave a marginally smaller value of ~0.6 pA. This indicates that the single-photon response corresponded to ~1% of the dark current, far larger than in cones though somewhat smaller than in most rods.

Taken together, the results of these two studies indicate that the electrical responses of Gekko gekko photoreceptors to illumination exhibit predominantly rod-like properties, though the amplitude of the single-photon response may not be quite as large as in true rods of other species.

Photoreceptor morphology. In an ultrastructural study, Röll (2000) showed conclusively that almost every morphological feature of the photoreceptors of nocturnal geckos is actually cone-like, confirming the original view of Walls (1934, 1942), and contradicting more recent assertions that they are rods. The only features that are rod-like relate to the outer segment, and are: (1) the large size of the outer segment, (2) the existence of outer segment 'discs' that for the most part are enclosed by the plasma membrane, and (3) the existence of an incisure. The cone-like features that she demonstrated in the photoreceptors from all species of gecko studied (both nocturnal and diurnal) were as follows: the connecting cilium was short; the inner segment contained a glycogen-rich paraboloid, and an ellipsoid (with oil droplets in diurnal species); the nuclei contained dispersed chromatin; and the synaptic terminals closely resembled cone pedicles. She concluded that "the retinae of nocturnal geckos have definitely to be classified as cone retinae".

The disc-like structure of the photoreceptor outer segment in the nocturnal gecko had previously been reported by Yoshida (1978), and the study of Röll (2000) was in close agreement. Yoshida (1978) stated that "as in other vertebrate rods, the stack of double membrane discs of the outer segment of the photoreceptor cells in the retina of adult [nocturnal] geckos is enclosed by the plasma membrane, except for the proximal zone of the outer segment". Both studies found the great majority of discs to be enclosed by plasma membrane, but both also reported frequent cone-like openings to the exterior, scattered along the length of the outer segment. Both also reported the existence of one (or rarely two) rod-like incisures.

Gekko opsins. The differences between cone and rod opsins were presented in Section 6. The two primary opsins of Gekko gekko have been shown to clade with the LWS and Rh2 cone opsins of other vertebrates, and to exhibit cone-like biochemical properties (Kojima et al, 1992). In particular, the gecko Rh2 opsin has the Q122 and P189 that have been reported to underlie the cone visual pigment properties of fast meta II decay and fast pigment regeneration (see Imai et al, 2005, and Section 6).

Gecko phototransduction cascade. The proteins of the transduction cascade in Gekko gekko were investigated by Zhang et al (2006) and, in all the proteins that they were able to identify, the sequences were cone-like rather than rod-like; those identified proteins comprised the α subunit of Gt (GNAT2), the catalytic and inhibitory subunits of the PDE6 (PDE6C and PDE6H), the α subunit of the cyclic nucleotide-gated channel (CNGA3), and arrestin (ARR3). Although these proteins were predominantly cone-like, a few residues were identified as being rod-like. On the other hand, in measuring expression levels and activities, they found that RGS9 was expressed at the low level expected for rods rather than the high level characteristic of cones, and the resulting GAP activity was correspondingly low; likewise, the low dark basal activity of the PDE was typical of rods rather than of cones.

Taken together, these results on the opsin and the cascade appear to indicate that the proteins of Gekko gekko photoreceptors are overwhelmingly cone-like, but that the expression levels and/or activities of at least two of the proteins that are important in generating slow responses (GAP activity and basal PDE activity) are instead rod-like.

Skate: Rods that can exhibit cone-like properties

Some deep-water species of skate have been shown to possess pure rod retinas, but their rods are able to function in a cone-like manner at intensities that would normally saturate rods (reviewed in Ripps & Dowling, 1991). The outer segments of the rods in these species have all the morphological and other features of classical rods, in terms of large cylindrical outer segment, sealed-off discs, microspectrophotometric peak at 500 nm, and band-like incorporation of labeled amino acid. On the other hand, the ultrastructure of the synaptic terminal is intermediate between that of conventional rods and cones, with multiple synaptic ribbons and contacts at both invaginating and flat contacts (reviewed in Dowling & Ripps, 1991).

The electrical responses of these cells were recorded by Dowling & Ripps (1972) using the aspartate-isolated trans-retinal potential from the isolated retina, which reflects photoreceptor activity. Under dark-adapted conditions the electrical responses closely resembled those of conventional rods. Furthermore, application of steady background illumination led to saturation at relatively low intensities, as in other rods. However, when these backgrounds were left on for extended periods the rods slowly recovered and were able to respond to incremental stimuli. For backgrounds of moderate intensity, a steady state of adaptation was reached within 5-10 min, but for more intense backgrounds the rods took 20 min or more to recover from saturation and to reach a steady adaptational state. Those findings from trans-retinal recordings were subsequently confirmed by suction pipette recordings from skate rods, under dark-adapted conditions and at a single moderately bright background intensity (Cornwall et al, 1989). The suction pipette measurements showed that the acceleration of the flash response that occurs when the cell recovers from the initial saturation involves speeding-up of each of the shut-off reactions, in much the same way as occurs in a conventional rod exposed to steady backgrounds or to temperature changes.

These results are consistent with the notion that rods in the skate all-rod retina function as conventional rods under fully dark-adapted conditions and in dim illumination. However, upon exposure to brighter steady backgrounds, the skate rods initially saturate but then recover after tens of minutes and display adaptational properties that are reminiscent of those of cones. Hence it would appear that, in this retina that lacks cones, the rods have become modified in a way that permits them to slowly change their response properties from rod-like to somewhat more cone-like. At present, the cellular and molecular mechanisms that enable this transition are not known.

In a conventional 'duplex' retina, containing both rods and cones, there is no need for the rods to function at moderate to high background intensities. Indeed, there is a distinct advantage in the rods becoming saturated at the intensities at which cones operate, because this reduces the metabolic load on the outer retina and permits the oxygen tension to be maintained at a reasonable level for the cones. But in the all-rod skate retina, it seems that the rods have had to forgo this energy-saving trick in order to enable the animal to continue to see at intensities that would otherwise be blinding.

What is needed to make a 'true rod'?

In light of the results presented in Section 10 and up to here in Section 11, the following interpretations are drawn regarding the crucial features that are needed to make a 'true rod', defined as one that reliably signals the occurrence of individual photoisomerizations, as distinct from a photoreceptor with cone-like properties:

H-1) First, the photoreceptor needs to express an opsin with a peak spectral sensitivity shorter than about 520 nm, in order to achieve a sufficiently low rate of thermal isomerizations; hence, LWS opsins are effectively ruled out.

H-2) The amplification of the phototransduction cascade does not need to differ significantly from that in a conventional cone.

H-3) However, one required change is that the shut-off reactions underlying response recovery need to be slow enough that the response to a single photoisomerization can build up sufficiently to suppress at least 1% (and preferably more) of the circulating dark current.

H-4) In comparison with typical cone shut-off, the required slowing necessitates concerted changes that: (1) slow the shut-off of R*; (2) slow the shut-off of G*/E*; (3) slow the cGMP turnover time by lowering the basal rate of PDE activity; and (4) slow the Ca2+-mediated negative feedback loop so that the recovery of cGMP levels and the re-opening of ion channels are slowed. It is not crucial whether these changes are achieved by alteration in the activities of the proteins, or by altered expression levels.

H-5) Secondly, the cytoplasmic messengers (cGMP and Ca2+) need to be able to diffuse substantial distances axially along the outer segment, and this requires a significant change in outer segment morphology: the sac membranes need to be enclosed by the plasma membrane (in effect forming discs) in a manner that provides an enlarged conduit for axially movement. In addition, one or more longitudinal incisures in the outer segment can further assist in axial diffusion.

H-6) An additional change that will assist in rendering the (now) large single-photon response detectable above the background noise is a lowering of the intrinsic fluctuations in the phototransduction process through increased stability of the proteins of the cascade.

H-7) Through the combination of all the above changes, it should be possible to convert a cone photoreceptor that is specialized for high-performance rapid photopic vision into a rod photoreceptor that can reliably signal individual photoisomerizations under dark-adapted conditions. An inevitable consequence of the slowing of shut-off reactions, though, will be that this cell saturates at low to moderate background intensities.

Timing of the emergence of rods

In Section 10 it was shown that modern SWS2 'cone' opsins have an exceedingly low rate of thermal isomerization, making them exceptionally well adapted to act as the photopigment in the green rods of amphibia. We cannot be certain that the ancestral SWS2 opsin was equally as stable as this. But, even if its thermal stability had been several orders of magnitude poorer, then that would have been entirely adequate to support reliable single-photon detection if that opsin had been expressed in a 'rod'. We can conclude that cone opsins (at least of the SWS2 variety) already exhibited thermal stability sufficient to enable single-photon detection before rhodopsin evolved, and therefore presumably before rods evolved. Hence, it would appear that thermal stability of the opsin molecule was not the limiting factor in the evolution of rods (at least, when 'rods' are characterized by their ability to detect single photons).

It seems clear that photoreceptors with certain rod-like features had evolved prior to the divergence of cyclostomes from the lineage leading to jawed vertebrates. Thus, hagfish photoreceptors have been reported to have discs enclosed by plasma membrane, and their peak spectral sensitivity is at 500 nm (Section 3). Likewise, one class of lamprey photoreceptor has a number of rod-like features, including the expression of an opsin that appears homologous with Rh1, though the cell also retains other cone-like features, both anatomically and electrophysiologically (Section 3). Unfortunately, though, it has not yet been discovered whether these lamprey photoreceptors are able to respond reliably to the absorption of individual photons of light ‐ in other words whether they achieve the ultimate sensitivity that is the defining feature of the 'true rods' of jawed vertebrates. If future experiments were to show that both hagfish and lamprey photoreceptors indeed meet this criterion, then this would be evidence in support of the notion that their common ancestor likewise possessed true rods.

Until this issue can be resolved, it is not possible to confidently go further than to say, firstly, that it seems highly probable that the last common ancestor of hagfish and lampreys possessed a class of photoreceptor with a number of rod-like features and, secondly, that 'true rods' had definitely evolved by the time that the first jawed vertebrates appeared.

Scenario for the emergence of 'true rod photoreceptors'

The following steps are proposed as the likely means by which rod photoreceptors emerged from their cone photoreceptor forerunners:

I-1) Following the '2R' rounds of whole-genome duplication, the lateral retina of an early vertebrate possessed five classes of cone-like photoreceptor cell, each expressing one of the five opsin classes (LWS, SWS1, SWS2, Rh2, Rh1).

I-2) In the photoreceptor expressing the Rh1 opsin, a number of changes gradually occurred, that led to a slowing of the response and concomitantly to an increase in its sensitivity.

I-3) These changes in the photoreceptor expressing Rh1 included slowing of the three shut-off reactions and slowing of the negative feedback loop. Some of these changes involved specialization of the shut-off proteins expressed in that cell, some involved altered expression levels, and some involved changes in morphology.

I-4) R* shut-off became slower, in part because of the slower decay of metarhodopsin II due to the mutations at residues 122 and 189, and in part through changes in the kinase and arrestin (GRK1 and ARR1).

I-5) G*/E* shut-off became slower primarily as a result of lowered levels of the RGS complex (RGS9-Gβ5-R9AP).

I-6) The turnover time for cGMP in darkness lengthened as a result of lowered resting phosphodiesterase activity, probably brought about by greater inhibition by the γ inhibitory subunits (PDE6G) in the αβγγ PDE complex.

I-7) The time constant for equilibration of cytoplasmic Ca2+ concentration increased in parallel, through a reduction in the number of Na+/Ca2+,K+ exchangers per unit volume of outer segment, in part as a result of lowered surface-to-volume ratio, and in part through an increase in cytoplasmic Ca2+-buffering power.

I-8) Changes at the rim of the outer segment lamellae led to the plasma membrane enclosing groups of lamellae (which thereby became groups of discs), providing an enhanced cross-sectional area for axial diffusion in the cytoplasm.

I-9) With these changes occurring gradually, but in concert, the photoreceptor expressing the Rh1 opsin would, over time, have become steadily slower and more sensitive.

I-10) Eventually almost the entire outer segment became sealed over, providing extensive longitudinal spread, and the shut-off reactions became sufficiently slow that the response to a single photoisomerization became large enough to exceed the level of noise in the cell.

I-11) Any further slowing of the shut-off reactions would then have been disadvantageous.

I-12) The synapse of this cell had a less demanding role, because the signal-to-noise ratio was higher and the kinetics were slower, and hence the synapse was able to function satisfactorily with less expenditure on synaptic machinery (i.e. with less extensive ribbon and fewer vesicles).

I-13) The eventual outcome of these combined gradual changes was the emergence of a 'true rod' photoreceptor, that reliably signaled individual photoisomerizations.

12. Retinoid re-isomerization in darkness

As discussed in Section 5, a major difference between vertebrate retinal photopigments and those of invertebrates is that the vertebrate visual opsins release their all-trans retinoid following light activation. The vertebrate retina therefore requires a continual supply of 11-cis retinal, in order to silence the residual activity of the free opsin and at the same time regenerate native rhodopsin for further signaling by light. This is accomplished by two biochemical pathways that operate in darkness (Fig. 27; reviewed in Lamb & Pugh, 2004; Wang & Kefalov, 2011; Saari, 2012). One is the classical 'retinoid cycle of vision' (Fig. 27B), in which all-trans retinoid is transported to the RPE, isomerized to the 11-cis isomer, and then transported back to the retina. The second is a less well understood pathway, internal to the retina, involving Müller cells and cone inner segments, that is thought to contribute to the regeneration of cone visual pigment.

Figure 27. Retinoid cycles: Overview of the two cycles, and flow in the RPE cycle. A, Overview of the flow of retinoid in the two cycles. The areas separated by solid lines represent cellular compartments of a retinal pigment epithelial cell (top), a rod and a cone photoreceptor cell (middle), and a Müller cell (bottom). The ovals surrounding 11-Ral represent rhodopsin (gray) and cone opsins (tricolor). Photoisomerization reactions are shown in red. All other chemical reactions are catalyzed by enzymes. Retinoids are chaperoned by retinoid-binding proteins (not shown) during intercellular and intracellular movement. Abbreviations: at-RE, all-trans retinyl esters; at-Ral, all-trans retinal; at-Rol, all-trans retinol (= vitamin A); 11-Ral, 11-cis retinal; 11-Rol, 11-cis retinol. From Saari (2012). B, Flow of retinoid in the RPE cycle. Delivery of 11-cis retinoid is shown by solid arrows, while removal of all-trans retinoid is shown by dashed arrows. Abbreviations: OS, outer segment; IPM, inter-photoreceptor matrix; RPE, retinal pigment epithelium; SER, smooth endoplasmic reticulum. RAL, retinaldehyde; ROL, retinol. For the chemical icons: AL, OL and E denote the aldehyde, alcohol, and ester groups attached to the retinoid hydrocarbon chain. Enzymes (in red): RDH, all-trans retinol dehydrogenase; LRAT; lecithin:retinol acyltransferase; RDH5, 11-cis retinol dehydrogenase. Chaperone proteins (in blue): IRBP, inter-photoreceptor retinol binding protein; CRBP, cellular retinol binding protein; RPE65, retinal pigment epithelium 65 kDa protein, now known to be the isomerohydrolase; CRALBP, cellular retinal binding protein. The ABCA4 transporter is not shown; this rescues the very small proportion of all-trans retinoid that inadvertently reaches the luminal leaflet of the disc membrane, and it has only a minor role in total retinoid cycling. From Lamb & Pugh (2006a). Gene names are given in boxes; see also Table 4.

Intra-retina retinoid cycle

Although most work on retinoid recycling over the past four decades has concentrated on the RPE cycle, the fact that cone photoreceptors pre-date rod photoreceptors raises the distinct possibility that the ancestral retinoid cycle of the vertebrate eye may have been the intra-retina cycle involving the cones and Müller cells, with the RPE cycle having evolved subsequently. The intra-retina cycle appears simpler, in that it involves isomerization of all-trans retinol (vitamin A) directly to 11-cis retinol (bottom of Fig. 27A), via an as-yet-unidentified isomerase II, without requiring initial esterification followed by an isomerohydrolase reaction (see Section 12). Unfortunately, though, as this cycle has been less intensively studied, and as the isomerase has not been identified, it has not yet proven possible to investigate the evolutionary roots of the cycle.

RPE retinoid cycle

Two recent papers have made important advances in determining the origin of the classical RPE retinoid cycle. Albalat (2012) and Poliakov et al (2012) have shown that this cycle is present only in vertebrates, as cephalochordates and tunicates do not possess the required enzymes, implying that the cycle evolved during the 100 million year interval from #4 to #5 in Fig. 1.

Two crucial enzymes in the retinoid cycle are LRAT (lecithin:retinol acyltransferase) and RPE65. LRAT esterifies vitamin A (all-trans retinol) to all-trans retinyl ester, which is the substrate for RPE65, which actually performs the isomerization while at the same time cleaving the ester bond, in a so-called 'isomerohydrolase' reaction. This step generates 11-cis retinol which is subsequently oxidized to the aldehyde, 11-cis retinal, and then transported to the retina.

Albalat (2012) undertook an in silico search for the genetic machinery of retinoid processing amongst invertebrates, and he analyzed the likely function of the components that he found. He concluded that "genome surveys, phylogenetic reconstructions and structural analyses of invertebrate components similar to those of the vertebrate retinoid cycle ‐ that is, Rdh8, Rdh12, Lrat, Rpe65, Rdh5, Rlbp1, and Rbp3 ‐ did not provide any evolutionary or functional support for the existence of the genetic machinery of the retinoid cycle outside vertebrates".

Poliakov et al (2012) extended that approach, by experimentally determining the functional activity of the key enzymes LRAT and RPE65 (and similar molecules) in lamprey and in tunicate. In lamprey (Petromyzon marinus), they showed that LRAT and RPE65 are both present and functional, and further that the key sites for RPE65's ability to act an isomerohydrolase are remarkably similar to those of jawed vertebrates. On the other hand, their phylogenetic analyses confirmed that neither RPE65 nor LRAT have orthologs in the cephalochordate (amphioxus) or the tunicate (Ciona intestinalis). They showed than an enzyme previously proposed (and named) as a Ciona ortholog of RPE65 by Takimoto et al (2006) has no isomerohydrolase activity, confirming the report of Kusakabe et al (2009), and they showed that it functions instead as a BCMO (β-carotene mono-oxygenase).

Taken together, these results show that both the crucial transition from a BCMO to a true RPE65 isomerohydrolase, and also the origin of LRAT, occurred only in the lineage leading to vertebrates (jawless and jawed), after the divergence of tunicates. Hence, the RPE retinoid cycle evolved only in vertebrates.

In a number of invertebrate species, it has been known for many years that rhodopsin can be regenerated in darkness (Stavenga, 1975), but there is scant evidence as to how this occurs. In Drosophila, evidence has recently been obtained for the possible existence of a retinoid cycle, though rather different from that in the RPE (Wang et al, 2010).

Scenario of the origin of retinoid recycling in the vertebrate retina/RPE

From our current knowledge of the intra-retinal and RPE retinoid cycles, it is possible to hypothesize the following scenario for the evolution of retinoid processing in the vertebrate eye:

J-1) At around the time that chordate ciliary opsins lost their bistable (photoreversible) properties and instead released their all-trans retinoid, an intra-retinal retinoid processing cycle arose, that utilized an isomerase (named isomerase II) in the Müller cells to isomerize retinol from its all-trans to its 11-cis form.

J-2) Subsequently, around the time that the RPE became specialized as a monolayer apposed to the retina, the two crucial enzymes LRAT and RPE65 evolved, and the RPE was able to adopt an additional role in retinoid re-isomerization.

Chapter I: [1. Introduction] [2. Origins] [3. Ciliary photoreceptors in the eyes of extant chordates] [4. Gradations in chordate eyes: retina and photoreceptors]
Chapter II: [5. Pre-vertebrate chordate C-opsins] [6. Vertebrate 'visual' opsins]
Chapter III: [7. Vertebrate retinal cones and rods] [8. Evolution of the vertebrate retinal phototransduction cascade] [9. Cones: Photoreceptors with exceptional performance] [10. Noise: Thermal isomerization and other sources of noise] [11. Rod specializations and the origin of rods] [12. Retinoid re-isomerization in darkness]
Chapter IV: [13. Development of the retina at a macroscopic level] [14. Molecular signatures and cell differentiation in the vertebrate retina] [15. Synaptic transmission from photoreceptors to ganglion cells] [16. Retinal processing: Bipolar cells and the photopic and scotopic pathways]
Chapter V: [17. When did spatial (imaging) vision arise in the chordate lineage?] [18. Conclusions: Scenario for the evolution of photoreceptors and the vertebrate retina] [19. Summary] [20. References]

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The author

Trevor D. Lamb received a degree in Electronic Engineering from Melbourne University in 1971 and then moved to Cambridge, UK, to do his graduate studies under the guidance of Sir Alan Hodgkin, working with Denis Baylor on retinal horizontal cells and photoreceptors. He received his PhD in 1975. Then as a post-doc at Stanford, USA, Denis Baylor, King-Wai Yau and Trevor developed the suction pipette technique for recording from photoreceptors. For the following 25 years he again worked in Cambridge, UK, on phototransduction and light- and dark-adaptation. He was elected a Fellow of the Royal Society in 1993. With Ed Pugh in the USA he developed a mathematical description of the molecular reactions underlying the photoreceptor light response, as well as a model of dark adaptation and the retinoid cycle. In 2003, Trevor returned to Australia, as a Federation Fellow at the Australian National University (ANU), in Canberra. Since 2011 he has been an Emeritus Professor at ANU, where he pursues his current interest in the evolutionary origin of photoreceptors and the retina. e-mail Trevor at Trevor.Lamb@anu.edu.au

May 2013