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The Journal of Neuroscience, November 5, 2003, 23(31):10100-10106

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Cellular/Molecular
Tyrosine Phosphorylation of Rod Cyclic Nucleotide-Gated Channels Switches Off Ca²⁺/Calmodulin Inhibition

Jeffrey L. Krajewski,^1,2 Charles W. Luetje,² and Richard H. Kramer¹

¹Deparment of Molecular and Cell Biology, University of California, Berkeley, California 94720, and ²Department of Molecular and Cellular Pharmacology, University of Miami, Miami, Florida 33101

Cyclic nucleotide-gated (CNG) ion channels are crucial for phototransduction in rod photoreceptors. Light triggers a biochemical cascade that reduces the concentration of cGMP in rods, closing CNG channels, which leads to membrane potential hyperpolarization and a decrease in the concentration of intracellular Ca²⁺. During light adaptation, the sensitivity of CNG channels to cGMP is decreased by Ca²⁺, which in conjunction with calmodulin (CaM), binds directly to CNG channels. The cGMP sensitivity of rod CNG channels is also reduced by phosphorylation of specific tyrosine residues in the three CNGA1 subunits and one CNGB1 subunit that comprise the rod channel. Here we show that phosphorylation prevents Ca²⁺/CaM inhibition. Experiments on native channels in rod outer segments and expressed channels in Xenopus oocytes show that Ca²⁺/CaM inhibition can be toggled off or on by promoting phosphorylation or dephosphorylation, respectively. Experiments in which the crucial tyrosine phosphorylation sites in CNGA1 and CNGB1 are replaced with phenylalanines show that residue Y498 in CNGA1 is the phosphorylation site responsible for regulating Ca²⁺/CaM inhibition. Ca²⁺/CaM inhibits the rod channel by binding to the N terminus of the CNGB1 subunit, causing it to uncouple from the C terminus of CNGA1. We propose that phosphorylation of CNGA1_Y498, on the C terminus of CNGA1, triggers an equivalent uncoupling from the C terminus of CNGB1, thereby curtailing Ca²⁺/CaM inhibition. The control of CaM inhibition by CNG channel phosphorylation may be important for light adaptation and the regulation of phototransduction by IGF-1, a retinal paracrine factor that alters the tyrosine phosphorylation state of rod CNG channels.

Key words: rod; photoreceptor; cGMP; channel; phosphorylation; calmodulin

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Received Aug 5, 2003; revised September 9, 2003; accepted September 12, 2003.

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