A quantitative account of the activation steps involved in phototransduction in amphibian photoreceptors.

Abstract

SUMMARY1. We have undertaken a theoretical analysis of the steps contributing to the phototransduction cascade in vertebrate photoreceptors. We have explicitly considered only the activation steps, i.e. we have not dealt with the inactivation reactions.2. From the theoretical analysis we conclude that a single photoisomerization leads to activation of the phosphodiesterase (PDE) with a time course which approximates a delayed ramp; the delay is contributed by several short first-order delay stages.3. We derive a method for extracting the time course of PDE activation from the measured electrical response, and we apply this method to recordings of the photoresponse from salamander rods. The results confirm the prediction that the time course of PDE activation is a delayed ramp, with slope proportional to light intensity; the initial delay is about 10-20 ms.4. We derive approximate analytical solutions for the electrical response of the photoreceptor to light, both for bright flashes (isotropic conditions) and for single photons (involving longitudinal diffusion of cyclic GMP in the outer segment). The response to a brief flash is predicted to follow a delayed Gaussian function of time, i.e. after an initial short delay the response should begin rising in proportion to t2. Further, the response-intensity relation is predicted to obey an exponential saturation.5. These predictions are compared with experiment, and it is shown that the rising phase of the flash response is accurately described over a very wide range of intensities. We conclude that the model provides a comprehensive description of the activation steps of phototransduction at a molecular level. INTROD-UCTIONThe molecular basis of phototransduction has been studied intensively over the last decade. The steps involved in initiation of the response (i.e. in activation) are now well understood at a molecular level, but in contrast considerable doubt still surrounds the details of the mechanisms involved in termination of the state of activation (i.e. in inactivation). In this paper we show that there is now sufficient M1S 9291 T. D. LAMB AND E. N. PUGH JR quantitative information about each of the processes involved in activation to enable us to develop a formal quantitative description.Our goal has been to provide a biophysical description of the rising phase of the photoresponse, applicable over an extremely wide range of intensities, from the level of single photoisomerizations upwards. To achieve this goal we have combined current knowledge of each of the molecular steps involved in initiating phototransduction. Our model (or set of equations) is explicit in molecular terms, and depicts the activation steps in phototransduction as a series of relatively simple physical and biochemical processes, for which most of the parameters are basic physical quantities.The concepts presented here represent a synthesis of ideas originating from many groups. We briefly summarize these ideas in the next section, but for a fuller treatment of the extensive literatur...

Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa

“…The leading edge of the a-waves was fit (as an ensemble; ref. 19) by the Lamb and Pugh model for the activation phase of the phototransduction cascade (20). The maximal response (Rmp 3 ) and the amplification constant (S) were calculated from this model.…”

[13] Electroretinographic determination of human Rod flash response in vivo

“…The dashed curve indicates the predicted response to a test flash of 3.5 × 10 3 sc td-sec; this curve was obtained by fitting (ensemble fit) a computational model of the a-wave leading edge to the family of waveforms. 9,40 Open circles positioned at the post-test-flash time of 13.8 msec indicate paired-flash determinations of A/A mo , the normalized derived rod response, at four test flash strengths (those for which the a-wave peak occurred later than 13.8 msec) including the 174-sc td-sec case described in Fig. 5B.…”

Input-Driven Components of Spike-Frequency Adaptation Can Be UnmaskedIn Vivo

“…These mechanisms of outputdriven and input-driven adaptation may have different biophysical origins compared with auditory receptor cells but could constitute analogous functional operations. Similarly, photoreceptors are influenced by several different adaptation mechanisms along the phototransduction pathway (Lamb and Pugh, 1992;Hardie and Raghu, 2001), and their relative contributions to light adaptation are of particular interest (Bownds and Arshavsky, 1995).…”