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Department of Physiology, School of Medicine, University of California at San Francisco, San Francisco, CA 94143

Address correspondence to Juan I. Korenbrot, Box 0444, Department of Physiology, University of California at San Francisco, San Francisco, CA 94143. Fax: (415) 476-4929; email: juan{at}itsa.ucsf.edu

In the mammalian retina, cone photoreceptors efficiently adapt to changing background light intensity and, therefore, are able to signal small differences in luminance between objects and backgrounds, even when the absolute intensity of the background changes over five to six orders of magnitude. Mammalian rod photoreceptors, in contrast, adapt very little and only at intensities that nearly saturate the amplitude of their photoresponse. In search of a molecular explanation for this observation we assessed Ca²⁺-dependent modulation of ligand sensitivity in cyclic GMP–gated (CNG) ion channels of intact mammalian rods and cones. Solitary photoreceptors were isolated by gentle proteolysis of ground squirrel retina. Rods and cones were distinguished by whether or not their outer segments bind PNA lectin. We measured membrane currents under voltage-clamp in photoreceptors loaded with Diazo-2, a caged Ca²⁺ chelator, and fixed concentrations of 8Br-cGMP. At 600 nM free cytoplasmic Ca²⁺ the midpoint of the cone CNG channels sensitivity to 8BrcGMP, ^8BrcGMPK_1/2, is 2.3 µM. The ligand sensitivity is less in rod than in cone channels. Instantly decreasing cytoplasmic Ca²⁺ to <30 nM activates a large inward membrane current in cones, but not in rods. Current activation arises from a Ca²⁺ -dependent modulation of cone CNG channels, presumably because of an increase in their affinity to the cyclic nucleotide. The time course of current activation is temperature dependent; it is well described by a single exponential process of 480 ms time constant at 20–21°C and 138 ms at 32°C. The absence of detectable Ca²⁺-dependent CNG current modulation in intact rods, in view of the known channel modulation by calmodulin in-vitro, affirms the modulation in intact rods may only occur at low Ca²⁺ concentrations, those expected at intensities that nearly saturate the rod photoresponse. The correspondence between Ca²⁺ dependence of CNG modulation and the ability to light adapt suggest these events are correlated in photoreceptors.

Key Words: retina • phototransduction • ion channel • signal transduction • light adaptation

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