sensitivity and adaptation in the retina

Sensitivity and Adaptation in the Retina

• Visual transduction

• single photon sensitivity

• dark current

• rhodopsin

• Ca++ vs cGMP as the messenger

• amplification

• Operating range of vision

• saturation, threshold, sensitivity, adaptation

• Ca++ role in adaptation

• Neuronal specialization: rods vs. cones

• expanding the operating range

• population encoding of color

Single photon detection in humans(Hecht, 1949)

Photoreceptor Layer of Frog Retina and Dark Current

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Fig. 1. Scanning electron micrograph of photoreceptor layer of frog retina (courtesy of W. H. Miller). Superimposed on a rod at right is a schematic diagram of the dark, circulating current. The lower panel show the mean (n = 99) photocurrent response of a toad rod in HEPES Ringers to 20 msec 520 nm flashes of intensity 0.029 hv .~rn-~. The individual responses of the rod to this flash show quanta1 fluctuations that can be attributed to Poisson fluctuations in photon absorptions, with a Poisson distribution mean of 0.53 events/flash (Baylor e/ al., 1979b). The lower panel can thus be taken to represent, approximately,

the single photon response, scaled to about 0.5 of its height.

1615

Dark Current

Retinal isomerization and rhodopsin

Ca++ vs cGMP

• Ca++ is the messenger

• external Ca++ suppresses dark current

• reversal potential close to Ca++

• iontophoretic inj of Ca++ hyperpolarizes and decreases light sensitivity

• Ca++ is not the messenger

• membrane very permeable to Ca++

• Ca++ chelator doesnʼt decrease light sensitivity

• free Ca++ decreases during light response


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• cGMP is the messenger

• injection induces rapid depolarization

• recovery from this depolarization speed up by light

• injection increases latency of light response

• BUT, could cGMP increase the dark current via Ca++


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1626 Ii. N. PCGH JR and W. H. Corms

five-fold. This result strengthened the conclusion that the cGMP-induced depolarizations observed by Miller, Nicol and others were due to an increase in the light-sensitive membrane current. A further advance was made by Matthews et al. (1985) and by Cobbs and Pugh (1985) who measured the outer segment membrane currents of isolated salamander rods with suction elec- trodes and infused cGMP into the rod via a voltage-clamping tight-seal pipette penetrating the inner segment, as shown in Fig. 5. These two latter reports showed that the inj~si~~ ~~~~~F could ~~p~d~y ~~c~~~se the light -sensitive mem - hrane current uf the outer segment I@-20 fold, and showed that the OS. membrane current which was induced by cGMP infusion was clearly an increase in the pre-infusion outer segment dark current.

Although the results cited in the last para- graph strengthened the conclusion that increase in outer segment cGMP led to the opening of ghr, and made it likely that the process that keeps g,,, open under normal conditions requires cGMP, they did not establish the mechanism by which cGMP leads to opening of g,,. All the

physiological studies cited in this section are logically consistent with the notion that cGMP increases the dark current vin :I calcium- pumping mechanism and that C&+ serves as the internal messenger. The statement in the last sentence. however, in no way is meant to deny the evidence cited earlier against <‘a’+ playing the role of excitational messenger, but merely to point out that the evidence cited 5~1 far favoring cGMP cannot be considered unequivocal.

THE DISCOVERY OF k,,, A EGMP-GATED CONDUCTANCE IN THE OUTER

SEGMENT MEMBRANE

A surprising and revolutionary mechanism for cGMP action was discovered by Fesenko et al. (1985). As shown in Fig. 6, they demon- strated that cGMP could act directly on the cytoplasmic face of excised patches of r.o.s. membrane to increase ionic permeability; CazL, by contrast, had no effect on the conductance of excised patches. The cGMP gating effect was o~rationally cooperative ~~- L. the cGMP-

cGMP-Sensitive Conductance of Rod Outer Segment Membrane

lOmV[

Fig. 6. (A) Scheme use by Fesenko et ui. (1985) in their discovery of a cGMP-gated conductance I” the rod outer segment membrane. A small patch of O.S. membrane was excised from the outer segment with the tight-seal technique of Neher and Sakman. (B) Voltages pulses were applied across the membrane patch and voltage-clamp currents measured under various perfusion conditions, one of which is illustrated. Application of cGMP in the perfusate altered the increased the current through the membrane patch. Ca2+ or calcium chelators applied to the patch had little effect. (C) The cGMP-concentration dependence of the membrane currents through patches as determined in (8). The smooth curve drawn through the data was generated with the Hill equation, equation (2) with k, = 30pM and N = I .8. (D) The same data as in (C) are plotted in the form lo&l/(1 - 1)] vs log[cGMP], where I is clamp current normalized by the maximal current induced by cGMP perfusion: the slope gives .N. the Hill cocilicient.

Fesenko et al. 1985

26 Investigative Ophthalmology 8c Visual Science, January 1994, Vol. 35, No. 1

Cone:

tion

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FIGURE 16. Experiments demonstrating that the Ca2+ feed-back does not underlie the di(Terences in sensitivity and re-sponse kineiics between rods and cones. Suction-pipet. re-cordings. In both top and bottom panels, filled circles indi-cate an electrical response to a dim Hash in normal Ringer'ssolution, and open circles indicate the response to an identi-cal Hash with the Ca2+ feedback removed. For both rods andcones, removing the negative feedback increases the lightsensitivity by threefold to (bin-fold and slows the lime-to-peak of the response, but the same differences between rodsand cones persist (note the different scales in top and bot-tom panels). Flash delivered 85 photons (620 run) /im~2 inupper panel and 2.2 photons (520 nm) nm~'2 in lower panel.Reprinted with permission from Nakatani K, Yau K-W. JPhysiol. J 989;409:525-548.

ubiquitous in cells, regardless of whether the stimulusis light, odorants, hormones, neurotransmitters, etc.Even visual pigments bear a striking structural similar-ity to other G protein-coupled membrane receptors,all having a signature seven-transmembrane-helix to-pology. The knowledge of phototransduction is so ad-vanced that it often serves as a model system to shedlight on other signal transduction pathways.

As it is, the phototransduction process seems al-ready well unfolded. However, like any complex cellu-

lar process, new components and side pathways willundoubtedly emerge with further probing. Even now,while most ingredients of phototransduction appearto have (alien into place, there are pieces of the puzzlethai are either still at large (such as the Ca2+-depen-dent regulator of the guanylate cyclase mentioned ear-lier) or in search of a well-characterized function (suchas protein kinasc C,lb2'163 the protein phosducin,188

and so on). At the same time, while cones appear tohave a similar phototransduction scheme as rods, theexact mechanisms underlying their low sensitivity andfast response kineiics still remain unclear. Other moresubtle differences between rods and cones may alsobecome evident upon closer examination. Most of theknown proteins in the rod cascade are now cloned.This structural information, combined with the de-tailed biochemical and physiological knowledge, setsthe stage for a molecular dissection of the transduc-tion mechanism (see 32 for a recent review). One ben-eficiary of such advances will certainly be the under-standing of genetic diseases affecting retinal photore-ceptors. Already, the underlying causes of some ofthese diseases have come to light based on existingknowledge (see, for example, .189-191). Finally, onehopes eventually to be able to describe the entire pho-totransduction process in a quantitative way. This willnot be an easy task because of the complexity of theprocess, but good progress is already being made inthis direction.31>192~195 The usefulness of a quantitativedescription is that it may often be the only practicalway to evaluate the relative importance of different,components or branches in a complex pathway.

Rh Rh' T, Rh'-P

GGDP G*GTP G GDP

PDEi PDE* PDEi

ACG = 0 A C G < 0 -(CHANNELopen) ( CHANNELcioso)

T4 • A CG = 0(CHANNELopon)

FIGURE 17. A schematic representation of the phototrans-duction cascade (with the Caa+ feedback not. included) tohighlight the importance of the decay time constants of theactive intermediates (7,, T2, and T3) and the basal rate ofmetabolic flux of cGMP in darkness (r4). G is transducin,and PDl^ ' s l n c inactive form of the phosphodiestera.se. As-terisks indicate the active intermediates. AC = 0 representsthe steady basal level of cGMP in darkness, and AG < 0indicates a decline in cGMP level. Overall gain of the cascade(and hence light sensitivity) depends on the multiplicativeproduct of the various T values.

Phototransduction cascade

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© 1988 Nature Publishing Group

Ca++ and rod adaptation

(Nakatani and Yau, 1988)

Single Photon Response Variability349

Figure 10. Molecular Schematic of the Reac-tions of Phototransduction

Species and steps are colored red for activa-tion, blue for inactivation, green for regula-tion. For activation, a photon (h�) isomerizesrhodopsin to its active formR*, now identifiedas metarhodopsin II (MII). R* catalyzes activa-tion of a G protein to G*, which binds to aneffector E protein, activating it to G*�E*. Theeffector is a phosphodiesterase, which hy-drolyzes cGMP (cG) in the cytoplasm, leadingto closure of ion channels at the plasmamem-brane (PM). For inactivation, R* binds RK andis phosphorylated to form MII�P. Arrestin(Arr) then binds, substantially completing theinactivation of R*. G*�E* is inactivated by

hydrolysis of the terminal phosphate of G��GTP, a reaction accelerated by an RGS protein (regulator of G protein signaling; He et al., 1998)that is probably complexed to the type 5 G protein � subunit (G�5; Makino et al., 1999). The inactive G and E then separate. cGMP is continuallyformed by guanylyl cyclase (GC). For regulation, closure of channels causes a drop in cytoplasmic Ca2� concentration, regulating the cascadein (at least) two locations. GC activity is modulated by an activating protein (AP) (Gorczyca et al., 1994). RK activity is modulated by recoverin(Rec) (Kawamura, 1993; Klenchin et al., 1995; Tanaka et al., 1995). For further discussion of the reactions, see Nikonov et al. (1998).

Another approach would be to consider the magni- think that more than one molecular step is likely to beinvolved. Thus, the binding of RK may cause partialtude of the coefficient of variation of the kinetics, as

was originally done for the coefficient of variation of the inactivation (Pulvermuller et al., 1993), and phosphoryla-tion may cause partial inactivation (Miller et al., 1986;amplitudes by Baylor et al. (1979). In general terms,

the coefficient of variation resulting from a chain of n Wilden et al., 1986), while arrestin binding appears likelyto cause substantially complete inactivation (Wilden etstochastic reactions will be of the order of (cv)2 ! 1/n if

each rate constant is of similar magnitude. Substituting al., 1986).Our interpretation of the lifetime histograms in Figuresour mean value of cv(tlife) ! 0.37, we obtain a rough

estimate for the required number of shutoff stages as 4 and 8 is that R* does not exhibit a fixed lifetime butthat instead, the rate constant of R* inactivation in-(1/0.37)2, or about 7, subject to the proviso that these

hypothetical stages have constant parameters. How- creases with time. A prime candidatemolecule for medi-ating an increase in the rate constant of R* shutoff wouldever, the actual number of stages involved might be

much smaller than this if their rate constants are not beRK, and twodistinctmechanisms are likely to contrib-ute. First, we think that feedback plays a significant role,constant—for example, if feedback occurs onto one or

more of the stages. and, as originally suggested by Torre et al. (1986), wethink that one of the feedbackmessengers is Ca2�. Thus,In view of these findings, we have asked: what is the

minimum number of stages that must be invoked in we propose that the local drop in Ca2� concentrationduring the single photon response shortens the R* life-the shutoff of R* in order to account for the observed

variability in kinetics? And as an extreme: is it possible time, most probably through the Ca-dependent declinein binding of recoverin to RK, which should steadilythat termination of R* activity in a single step could

explain the results? To examine this question, we under- increase the amount of RK available for binding andphosphorylating R* as Ca2� declines (Kawamura, 1993;took simulations of a model of stochastic R* shutoff,

and we found that the simulated responses (Figure 9) Klenchin et al., 1995). Second, we suggest that activa-tion of RK by R* during the light response (Fowles etwere closely comparable to the behavior of real cells.

From this finding,we conclude that it is not in fact neces- al., 1988) might also play an important role.In addition to the effects onR* lifetime, any intermolec-sary to invoke a long series of stepwise reductions in

the activity of an individual R* molecule in order to ac- ular interactions that appeared to render R*’s activitygraded would lead to more reproducible single photoncount for the experimental results. Instead, we think that

the experimental results are likely to be explicable by a response kinetics. For example, if the binding betweenRK and R* were rapidly reversible, then as the amountscheme in which R* is inactivated by the presently

known reactions, as explained below. of RK available for binding increased, R* would appearto exhibit gradually declining activity. Similarly, a localaccumulation of GDP (asG* is activated)might graduallyPossible Molecular Mechanism

The known reactions of transduction are summarized reduce the apparent activity of R*. Taken in combination,it seems entirely plausible to us that modulation of R*in schematic form in Figure 10. As is well documented,

the shutoff of R* is mediated initially by the interaction of lifetime and activity by established mechanisms couldreduce the overall variability in single photon kineticsR* with RK, and subsequently, by the binding of arrestin

(Wilden et al., 1986). In our analysis and modeling, we to the degree actually observed.adopted the extreme assumption that the activity of R*is totally shut off in a single reaction step—yet even this Conclusions

In summary, our recordings show that the single photonextreme assumption provided a surprisingly accurateaccount, both of the individual response kinetics (Figure responses of rod photoreceptors are not stereotypical

in shape but that instead, they appear to inactivate over3) and of the overall variability (Figure 9). In reality, we

Ca++ and rod adaptation


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The central molecule in phototransduction is the sec-ond messenger, cGMP. All aspects of visual signalingare dictated by the balance between its synthesis anddegradation in the cytoplasm of the photoreceptor outersegment:

GTP!!!!cyclasecGMP

echannels

!!!!PDEGMP

cGMP synthesis is accomplished by guanylate cyclase,whereas cGMP hydrolysis is performed by cGMP phos-phodiesterase (PDE, also known as PDE6). In the dark-adapted photoreceptor, the balance between cGMPsynthesis and hydrolysis produces a steady-state levelof cGMP concentration. The free cGMP concentration isconstantly monitored by cGMP-gated cation channelslocated in the outer segment plasma membrane. The in-ward current through these channels keeps the cell par-tially depolarized. In the presence of light, cGMP levelsdecline as a result of PDE activation, which causes chan-nels to close and the cell to hyperpolarize. This hyperpo-larization slows neurotransmitter release from the syn-aptic terminal, signaling the presence of light to thesecondary neurons in the retina.Examples of photoresponses of mammalian rods andcones are shown in Figure 1. Although their light depen-dency and time course differ considerably, photores-ponses of both photoreceptor types are produced by

a transient decrease in cGMP concentration, mediatedby three categories ofmolecular events: cascade activa-tion, cascade inactivation, andcGMPrestoration. The in-terplay among these reactions determines the responsetime course and the photoreceptor’s sensitivity to light.Phototransduction Cascade: Activation and SignalAmplificationThe first event in vision is the absorption of a photon byrhodopsin (or cone opsin), which causes the cis-transisomerization of its chromophore, 11-cis-retinal, anda conformational change to its active state (known asMetarhodopsin II or R*). Within a millisecond of photoncapture, R* begins activating molecules of the G proteintransducin by catalyzing GDP/GTP exchange on trans-ducin’s a subunit (Gat) (Figure 2). Gat$GTP stimulatesPDE activity by binding to the g subunit of PDE, therebyreleasing this subunit’s inhibitory constraint on the cat-alytic a and b subunits of PDE. Activated PDE decreasesthe cGMP concentration in the photoreceptor cyto-plasm, leading to channel closure. One hallmark of thephototransduction cascade is the high degree of signalamplification achieved at these steps.

Signal amplification at the first stage of the cascade isachieved by the activation of many transducins by a sin-gle R*. The rate of transducin activation approaches 150turnovers per second in amphibian rods (Leskov et al.,2000) and is likely to bew2-fold higher in warm-bloodedanimals (Heck and Hofmann, 2001). Thus, a few tens ofGat$GTP molecules are produced in the course of amammalian rod’s response. This rate is much higherthan those measured in other G protein signaling path-ways (e.g., Mukhopadhyay and Ross, 1999; Bhandawatet al., 2005), which makes it a benchmark for the speedat which G proteins could be activated by GPCRs.

Equally important is the degree of signal amplificationprovided by activated PDE, which is one of a handful ofenzymes whose catalytic activity is so high that it is lim-ited primarily by the rate of cGMP diffusion into the cat-alytic site. The activation of just one of its catalytic sub-units by transducin in a frog rod causes the hydrolysis ofat least 600 cGMP molecules per second (Leskov et al.,2000), assuming dark-adapted amphibian rod outersegments containw4 mMcGMP (Pugh and Lamb, 2000).

Finally, additional signal amplification arises from theproperties of the cGMP-gated channels. Because theHill coefficient for channel opening by cGMP is w3, alight-induced decrease in the inward current is w3-foldlarger than the decrease in cGMP concentration. Collec-tively, these amplification mechanisms ensure the highsensitivity of vertebrate vision, including the ability ofrods to signal the absorption of single photons (Bayloret al., 1979).Phototransduction Cascade: InactivationAfter the photoresponse reaches its peak, the inwardcurrent rapidly returns to the dark level (Figure 1). Timelyrecovery is essential for the photoreceptor to generateresponses to subsequently absorbed photons, and tosignal rapid changes in illumination. Recovery to thedark state requires efficient termination of each amplifi-cation step of the phototransduction cascade, and therate at which these steps are inactivated sets the timecourse of the photoresponse.

In principle, termination of transducin activation couldbe achieved via the thermal decay of R*, but the rate of

Figure 1. Schematics of Rod and Cone Photoreceptors

Photon absorption in the outer segments of a rod and a cone causesa decrease in cGMP-gated inward currents (top traces). The outersegment currents of cones are appreciably faster than those ofrods and require flashes of higher intensity. The resulting membranehyperpolarization (bottom traces) is filtered by the electrical prop-erties of the photoreceptor membranes, including voltage-gatedconductances located in the inner segments. This hyperpolarizationslows neurotransmitter release from the synaptic terminals. Alltraces are schematic representations of responses to dim (thin)and bright (thick) brief flashes, and although generalizable to manydifferent species, are shown here with scale bars that reflect theaverage properties of primate photoreceptors (Baylor et al., 1984b;Schneeweis and Schnapf, 1995, 1999), ignoring the effects of photo-receptor coupling. OS, outer segment; IS, inner segment; N, nucleus;ST, synaptic terminal.

Neuron388



Rod Adaptation Cone Adaptation

(Nakatani and Yau, 1988)

Single Photon Response Variability349

Figure 10. Molecular Schematic of the Reac-tions of Phototransduction

Species and steps are colored red for activa-tion, blue for inactivation, green for regula-tion. For activation, a photon (h�) isomerizesrhodopsin to its active formR*, now identifiedas metarhodopsin II (MII). R* catalyzes activa-tion of a G protein to G*, which binds to aneffector E protein, activating it to G*�E*. Theeffector is a phosphodiesterase, which hy-drolyzes cGMP (cG) in the cytoplasm, leadingto closure of ion channels at the plasmamem-brane (PM). For inactivation, R* binds RK andis phosphorylated to form MII�P. Arrestin(Arr) then binds, substantially completing theinactivation of R*. G*�E* is inactivated by

hydrolysis of the terminal phosphate of G��GTP, a reaction accelerated by an RGS protein (regulator of G protein signaling; He et al., 1998)that is probably complexed to the type 5 G protein � subunit (G�5; Makino et al., 1999). The inactive G and E then separate. cGMP is continuallyformed by guanylyl cyclase (GC). For regulation, closure of channels causes a drop in cytoplasmic Ca2� concentration, regulating the cascadein (at least) two locations. GC activity is modulated by an activating protein (AP) (Gorczyca et al., 1994). RK activity is modulated by recoverin(Rec) (Kawamura, 1993; Klenchin et al., 1995; Tanaka et al., 1995). For further discussion of the reactions, see Nikonov et al. (1998).

Another approach would be to consider the magni- think that more than one molecular step is likely to beinvolved. Thus, the binding of RK may cause partialtude of the coefficient of variation of the kinetics, as

was originally done for the coefficient of variation of the inactivation (Pulvermuller et al., 1993), and phosphoryla-tion may cause partial inactivation (Miller et al., 1986;amplitudes by Baylor et al. (1979). In general terms,

the coefficient of variation resulting from a chain of n Wilden et al., 1986), while arrestin binding appears likelyto cause substantially complete inactivation (Wilden etstochastic reactions will be of the order of (cv)2 ! 1/n if

each rate constant is of similar magnitude. Substituting al., 1986).Our interpretation of the lifetime histograms in Figuresour mean value of cv(tlife) ! 0.37, we obtain a rough

estimate for the required number of shutoff stages as 4 and 8 is that R* does not exhibit a fixed lifetime butthat instead, the rate constant of R* inactivation in-(1/0.37)2, or about 7, subject to the proviso that these

hypothetical stages have constant parameters. How- creases with time. A prime candidatemolecule for medi-ating an increase in the rate constant of R* shutoff wouldever, the actual number of stages involved might be

much smaller than this if their rate constants are not beRK, and twodistinctmechanisms are likely to contrib-ute. First, we think that feedback plays a significant role,constant—for example, if feedback occurs onto one or

more of the stages. and, as originally suggested by Torre et al. (1986), wethink that one of the feedbackmessengers is Ca2�. Thus,In view of these findings, we have asked: what is the

minimum number of stages that must be invoked in we propose that the local drop in Ca2� concentrationduring the single photon response shortens the R* life-the shutoff of R* in order to account for the observed

variability in kinetics? And as an extreme: is it possible time, most probably through the Ca-dependent declinein binding of recoverin to RK, which should steadilythat termination of R* activity in a single step could

explain the results? To examine this question, we under- increase the amount of RK available for binding andphosphorylating R* as Ca2� declines (Kawamura, 1993;took simulations of a model of stochastic R* shutoff,

and we found that the simulated responses (Figure 9) Klenchin et al., 1995). Second, we suggest that activa-tion of RK by R* during the light response (Fowles etwere closely comparable to the behavior of real cells.

From this finding,we conclude that it is not in fact neces- al., 1988) might also play an important role.In addition to the effects onR* lifetime, any intermolec-sary to invoke a long series of stepwise reductions in

the activity of an individual R* molecule in order to ac- ular interactions that appeared to render R*’s activitygraded would lead to more reproducible single photoncount for the experimental results. Instead, we think that

the experimental results are likely to be explicable by a response kinetics. For example, if the binding betweenRK and R* were rapidly reversible, then as the amountscheme in which R* is inactivated by the presently

known reactions, as explained below. of RK available for binding increased, R* would appearto exhibit gradually declining activity. Similarly, a localaccumulation of GDP (asG* is activated)might graduallyPossible Molecular Mechanism

The known reactions of transduction are summarized reduce the apparent activity of R*. Taken in combination,it seems entirely plausible to us that modulation of R*in schematic form in Figure 10. As is well documented,

the shutoff of R* is mediated initially by the interaction of lifetime and activity by established mechanisms couldreduce the overall variability in single photon kineticsR* with RK, and subsequently, by the binding of arrestin

(Wilden et al., 1986). In our analysis and modeling, we to the degree actually observed.adopted the extreme assumption that the activity of R*is totally shut off in a single reaction step—yet even this Conclusions

In summary, our recordings show that the single photonextreme assumption provided a surprisingly accurateaccount, both of the individual response kinetics (Figure responses of rod photoreceptors are not stereotypical

in shape but that instead, they appear to inactivate over3) and of the overall variability (Figure 9). In reality, we

Activation, deactivation, regulation


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