Functional EF-Hands in Neuronal Calcium Sensor GCAP2 Determine Its Phosphorylation State and Subcellular Distribution , and Are Essential for Photoreceptor Cell Integrity

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Visual perception is initiated at retinal photoreceptor cells, where light activates an enzymatic cascade that reduces free cGMP. As cGMP drops, cGMP-channels close and reduce the inward current –including Ca2+ influx– so that photoreceptors hyperpolarize and emit a signal. As the light extinguishes, cGMP levels are restored to reestablish sensitivity. cGMP synthesis relies on guanylate cyclase/guanylate cyclase activating protein (RetGC/GCAP) complexes. GCAPs link the rate of cGMP synthesis to intracellular Ca2+ levels, by switching between a Ca2+-free state that activates cGMP synthesis during light exposure, and a Ca2+-bound state that arrests cGMP synthesis in the dark. It is established that GCAP1 mutations linked to adCORD disrupt this tight Ca2+ control of the cGMP levels. We here show that a GCAP2 functional transition from the Ca2+-free to the Ca2+-loaded form is essential for photoreceptor cell integrity, by a non-related mechanism. We show that GCAP2 locked in its Ca2+-free form is retained by phosphorylation and 14-3-3 binding to the proximal rod compartments, causing severe cell damage. This study identifies a pathway by which a sustained reduction in intracellular free Ca2+ could result in photoreceptor damage, relevant for light damage and for those genetic disorders resulting in “equivalent-light” scenarios.

Vyšlo v časopise: Functional EF-Hands in Neuronal Calcium Sensor GCAP2 Determine Its Phosphorylation State and Subcellular Distribution , and Are Essential for Photoreceptor Cell Integrity. PLoS Genet 10(7): e32767. doi:10.1371/journal.pgen.1004480
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004480

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