Variability in Single Photon Minireview Responses: A Cut in the Gordian Knot of Rod Phototransduction?

In a classic pair of papers, Baylor et al. (1979a, 1979b) Whitlock and Lamb employed the same preparation achieved the enduring feat of recording the responses as Rieke and Baylor—isolated rods from the toad Bufo of individual rods of the toad to extremely dim flashes marinus—and in all aspects where the data and analyses and proving that they were indeed generated in re- of the two investigations can be compared, the results sponse to single photons. In the intervening two de- appear in remarkable agreement. Both studies analyzed cades, single-photon responses have been recorded much larger ensembles of dim-flash trials than previous from the rods of many species, including those of pri- investigations (300-600 trials per individual rod, as op- mates (Baylor et al., 1984; Schneeweis and Schnapf, posed to typically 100-150 in previous studies). Both 1995). And in that same period, the project of under- studies confirm the original observation that the distri- standing the machinery that endows rods with their bution of response amplitudes at the time to peak of amazing ability has captivated and motivated a genera- the ensemble mean is quantized (Baylor et al., 1979b); tion of photoreceptor physiologists, biochemists, and that is, the histogram of amplitudes follows the Poisson molecular biologists. As a consequence, through the distribution dictated by photon capture statistics, ap- efforts of many investigators the molecular mechanisms propriately combined with dark noise, and with random of the G protein cascade of rod phototransduction have fluctuations in the amplitude of the single-photon re- been worked out in wondrous detail. In particular, a sponse (designated hereafter as singletons, as in Whit- generally accepted description of the amplifying events lock and Lamb's paper). Both studies find the variation underlying the activation phase of the single-photon in the singleton amplitude to be modest: the coefficient response has been achieved (Figure 1). And while insight of variation (cv) reported in both papers is about 20% into the molecular mechanisms governing the cascade's (the cv is the ratio of standard deviation to mean). Both timely inactivation has lagged behind that into the mech- studies find that calcium clamping (or calcium buffering) anisms governing activation, it is now rapidly catching leads to slowed responses with greater peak ampli- up. Nonetheless, full understanding of the inactivation tudes, and that the time to peak of the singletons under of the rod cascade has been bound up in a Gordian both conditions has a cv of 20%. And finally, both stud- knot—the apparent stereotypy of single-photon re- ies agree on an observation crucial to the understanding sponses. of the mechanism of R* shutoff: the cv of the singleton In this issue of Neuron, Whitlock and Lamb (1999) amplitudes measured under calcium clamping (or cal- appear to have cut the knot by providing compelling cium-buffered) conditions is approximately 20%, about evidence that the inactivation phase of toad rod single- the same as that obtained in the control condition. photon responses is in fact considerably more variable Though the two studies are in close factual agree- than previously thought. Moreover, based on their evi- ment, they differ in the analyses they apply. Whitlock dence, Whitlock and Lamb develop a persuasive case and Lamb separate variations in the gain of the initial that the lifetime of activated rhodopsin (R *