The illumination at the earth's surface varies by >10 orders of magnitude during the normal daynight cycle, and the vertebrate visual system covers this entire range of light intensities with two neuronal subsystems that rely on the activity of two types of photoreceptor cells, rods and cones. Human rod vision operates over approximately seven decimal orders of illumination. The cone visual system operates over an even wider range (
The molecular mechanisms underlying light adaptation may be discussed in the context of the reactions governing cGMP in the photoreceptor cytoplasm (
The intracellular concentration of cGMP is determined by the rate of its synthesis by the guanylyl cyclase and the rate of its hydrolysis by the cGMP phosphodiesterase (PDE). This concentration is constantly monitored by the cGMP-gated channels located in the photoreceptor plasma membrane. In the dark-adapted photoreceptor, a steady cGMP concentration of a few micromolars is maintained. This keeps a fraction of the cGMP-gated cationic channels of the outer plasma membrane open and the cell depolarized. Light causes cGMP to fall by activating PDE via the enzymatic cascade including photoactivated rhodopsin, the G-protein called transducin, and the effector enzyme PDE. The reduction in the cGMP concentration results in channel closure and photoreceptor hyperpolarization. Recovery of the light response occurs when the excitatory cascade is inactivated, cGMP level is restored by guanylyl cyclase, and the channels reopen. During photoresponse, the intracellular Ca2+ concentration also declines since its entry through the cGMP-gated channels is blocked while it continues to be extruded by a Na2+/Ca2+-K+, exchange molecule located in the plasma membrane. It is this Ca2+ decline that has been implicated as the main factor underlying light adaptation because it leads to the feedback regulation of various phototransduction cascade components.
To illustrate the importance of light adaptation to normal photoreceptor function, consider the following. For rod photoreceptors to register minimal light stimuli, a high degree of signal amplification has to be achieved in the rhodopsin-transducin-PDE cascade. For example, at the peak of the toad rod response to a single photon, which occurs 1 s after photon absorption,
5% of the open, light-sensitive channels become closed. This implies that steady illumination delivering only
100 photons per second would close all of the channels, rendering the cell unresponsive to any further light stimulation. But because rods adapt to light, this saturation is avoided until the ambient illumination produces a photon capture rate of
10,000 photons per second. The effect of adaptation is even more profound in cones: they virtually never saturate.
The transition between the dark- and the light-adapted states of the photoreceptor is accompanied by two significant changes in the physiological properties of photoreceptors. First, light-adapted photoreceptors are less sensitive to light, preventing them from becoming blind at high light intensity levels. Second, light-adapted photoreceptors produce quicker photoresponses, improving the temporal resolution in the visual system. It is to these two features that the term "light adaptation" has been most often applied, and the prevailing view in the literature suggests that the Ca2+ feedback systems underlie both. One immensely important contribution of
One effect of steady PDE activation on the absolute response sensitivity is rather straightforward. Since the absolute sensitivity of the response is proportional to the absolute number of the channels open before the flash, the reduction in the number of open channels caused by the steady illumination automatically leads to a compression of the response amplitude. However, the response compression is a relatively small part of the total effect of steady PDE activation. The main source of flash sensitivity reduction is due to acceleration of signal recovery caused by the PDE activation. Formally, this acceleration occurs because the time constant of the reaction governing flash-induced cGMP change is inversely proportional to the specific PDE activity per cytoplasmic volume. This time constant is exactly the same time constant that governs the turnover of the entire cGMP cytoplasmic pool under the same illumination conditions.
The latter concept is not intuitive, and , according to
In this analogy, a flash response is represented by the introduction of a brief, transient decrease in R(I). This causes the voltage to drop to a certain level, and then it exponentially returns back to the steady level with a time constant = RC. Since 1/RC is equivalent to the ratio of the steady state activity of PDE to the cytoplasmic volume (ß, according to
The accelerated recovery means that the flash response develops over a shorter period of time, and this reduces the sensitivity to a flash superimposed on a steady background. Thus, the steady state PDE activation reduces the sensitivity of the photoreceptor by the combined effects of reducing the fraction of open channels and by cutting the photoresponse short. Elegant experiments allowed 100-fold reduction in the flash sensitivity observed with their brightest background intensities (see Fig. 6 in
5-fold is due to the response compression and
15-fold is due to the kinetic effect of PDE activation, with the residual likely due to the effect of recoverin acting on the activated rhodopsin lifetime.
Having attributed the major portion of the reduction in photoreceptor sensitivity and the acceleration of the photoresponse to the elevated PDE activity before the flash, the question arises: what role does Ca2+ feedback play in light adaptation? The answer is clear when we keep in mind that the steady PDE activity produced by the background light causes a substantial increase in the cGMP hydrolytic activity. If there were no compensating mechanisms, cGMP concentration would be dramatically reduced, even under moderate background illumination, eventually leaving no channels open to register further light changes. Thus, the most fundamental role of Ca2+ in light adaptation is to oppose this saturation by engaging a number of molecular mechanisms that ultimately lead to the reopening of channels and, therefore, to the extension of the range of light intensities over which the photoreceptor operates (see
The major range-extending effect of Ca2+ is mediated by a feedback onto guanylyl cyclase through the Ca2+ binding proteins called guanylyl cyclase activating proteins. Light-dependent Ca2+ decline causes an increase in the rate of cGMP synthesis that counteracts the elevated steady PDE activity during background illumination. This effect of steady background light should not be confused with the dynamic Ca2+ feedback on guanylyl cyclase during the flash response that speeds up the flash response recovery.
The second range-extending effect of Ca2+ targets the cGMP-gated channels directly. Ca2+ decline causes the channels to become more sensitive to cGMP, so that they operate at lower cGMP concentration. This effect is likely mediated by calmodulin or calmodulin-like proteins, and appears to be more significant in cones than in rods (
The third Ca2+ feedback differs from the others because it causes both a range extension and contributes to the desensitization of the cell. Ca2+ decline enhances rhodopsin phosphorylation through the Ca2+-binding protein recoverin, leading to a decrease in the lifetime of the activated rhodopsin. This results in desensitization because it reduces the number of PDE molecules activated by each rhodopsin. The operating range is also extended because the reduced number of active PDEs translates into a reduced steady cGMP hydrolytic rate. Both Nikonov et al. and other recent literature discussed by the authors demonstrate that, in rods, this mechanism appears to be much less potent than the feedback onto the guanylyl cyclase.
Another important result reported in the their article is that there is no indication of a fourth proposed Ca2+ feedback mechanism, the adaptive regulation of the gain in the cascade between rhodopsin activation and channel closure.
Nikonov and colleagues now put forth the view that Ca2+ feedback in light adaptation serves almost exclusively to increase photoreceptor sensitivity rather than as a mechanism of photoreceptor desensitization. Although this may sound paradoxical, the sensitizing effect of the Ca2+ feedbackmediated range extension was evident from the very first publications that demonstrated the importance of light-induced Ca2+ decline for light adaptation (100-fold (see Figure 2 in
This brings us back to the definition of light adaptation in photoreceptors. As we mentioned above, adaptation is usually defined as a combination of cell desensitization and response acceleration. The logic of
With the quantitative description of phototransduction and light adaptation that Nikonov et al. provide, what is left unknown? We provide the following three examples here. First, although Nikonov et al. found no evidence for regulation of the phototransduction gain under their experimental conditions, it remains to be seen whether or not gain regulation occurs at higher illumination levels, on a longer time scale, or in different species. If it does, it would imply the existence of additional biochemical mechanisms and molecular components that are not included in the present scheme of phototransduction. Second, little is known about the molecular mechanisms that underlie light adaptation in cones. Cones are able to cover a wider range than rods, and are virtually impossible to saturate with continuous background light. Future studies should be directed towards understanding if the entire cone adaptation could be accounted for by perhaps more efficient rod-like adaptation mechanisms, or if it requires additional unique mechanisms. Third, on a higher level of the visual processing, it is unknown how adaptation of individual photoreceptors contributes to adaptation of the entire visual system. It remains to be determined how any of the three components of photoreceptor light adaptation, cell desensitization, response acceleration, and sensitivity range extension, may cause our light-adapted vision to work faster, with better contrast sensitivity and higher spatial resolution.
Submitted: 27 October 2000
Revised: 30 October 2000
Accepted: 30 October 2000
![]() |
References |
---|
![]() ![]() |
---|
Detwiler, P.B., and Gray-Keller, M.P. 1992. Some unresolved issues in physiology and biochemistry of phototransduction. Curr. Biol. 2:433-438[Medline].
Hodgkin, A.L., and Nunn, B.J. 1988. Control of light-sensitive current in salamander rods. J. Physiol. 403:439-471[Abstract].
Lagnado, L., and Baylor, D.A. 1992. Signal flow in visual transduction. Neuron. 8:995-1002[Medline].
Lamb, T.D., and Pugh, E.N., Jr. 1992. A quantitative account of the activation steps involved in phototransduction in amphibian photoreceptors. J. Physiol. 449:719-758[Abstract].
Matthews, H.R., Murphy, R.L.W., Fain, G.L., and Lamb, T.D. 1988. Photoreceptor light adaptation is mediated by cytoplasmic calcium-concentration. Nature. 334:67-69[Medline].
Nakatani, K., and Yau, K.W. 1988. Calcium and light adaptation in retinal rods and cones. Nature. 334:69-71[Medline].
Nikonov, S., Engheta, H., and Pugh, E.N., Jr. 1998. Kinetics of recovery of the dark-adapted salamander rod photoresponse. J. Gen. Physiol. 111:7-37
Nikonov, S., Lamb, T.D., and Pugh, E.N., Jr. 2000. The role of steady phosphodiesterase activity in the kinetics and sensitivity of the light-adapted salamander rod response. J. Gen. Physiol. 116:795-824
Pugh, E.N., Jr., Nikonov, S., and Lamb, T.D. 1999. Molecular mechanisms of vertebrate photoreceptor light adaptation. Curr. Opin. Neurobiol. 9:410-418[Medline].
Rebrik, T.A., Kotelnikova, E.A., and Korenbrot, J.I. 2000. Time course and Ca2+ dependence of sensitivity modulation in cyclic GMP-gated currents of intact cone photoreceptors. J. Gen. Physiol. 116:521-534
Rodieck, R.W. 1998. The First Steps in Seeing. Sunderland, MA, Sinauer Associates, Inc, pp. 562 pp.
|
|