Mg2+/Ca2+ cation binding cycle of guanylyl cyclase activating proteins (GCAPs): role in regulation of photoreceptor guanylyl cyclase

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Abstract
Photon absorption by photoreceptors activates hydrolysis of cGMP, which shuts down cGMP-gated channels and decreases free Ca2+ concentrations in outer segment. Suppression of Ca2+ influx through the cGMP channel by light activates retinal guanylyl cyclase through guanylyl cyclase activating proteins (GCAPs) and thus expedites photoreceptors recovery from excitation and restores their light sensitivity. GCAP1 and GCAP2, two ubiquitous among vertebrate species isoforms of GCAPs that activate retGC during rod response to light, are myristoylated Ca2+/Mg2+-binding proteins of the EF-hand superfamily. They consist of one non-metal binding EF-hand-like domain and three other EF-hands, each capable of binding Ca2+ and Mg2+. In the metal binding EF-hands of GCAP1, different point mutations can selectively block binding of Ca2+ or both Ca2+ and Mg2+ altogether. Activation of retGC at low Ca2+ (light adaptation) or its inhibition at high Ca2+ (dark adaptation) follows a cycle of Ca2+/Mg2+ exchange in GCAPs, rather than release of Ca2+ and its binding by apo-GCAPs. The Mg2+ binding in two of the EF-hands controls docking of GCAP1 with retGC1 in the conditions of light adaptation and is essential for activation of retGC. Mg2+ binding in a C-terminal EF-hand contributes to neither retGC1 docking with the cyclase nor its subsequent activation in the light, but is specifically required for switching the cyclase off in the conditions of dark adaptation by binding Ca2+. The Mg2+/Ca2+ exchange in GCAP1 and 2 operates within different range of intracellular Ca2+ concentrations and provides a two-step activation of the cyclase during rod recovery.

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