Abstract
Phosphodiesterase-6 (PDE6) is a key protein in the G-protein cascade converting photon information to bioelectrical signals in vertebrate photoreceptor cells. Here, we demonstrate that PDE6 is regulated by calcium, contrary to the common view that PDE1 is the unique PDE class whose activity is modulated by intracellular Ca2+. To broaden the operating range of photoreceptors, mammalian rod photoresponse recovery is accelerated mainly by two calcium sensor proteins: recoverin, modulating the lifetime of activated rhodopsin, and guanylate cyclase-activating proteins (GCAPs), regulating the cGMP synthesis. We found that decreasing rod intracellular Ca2+ concentration accelerates the flash response recovery and increases the basal PDE6 activity (βdark) maximally by ~ 30% when recording local electroretinography across the rod outer segment layer from GCAPs−/− recoverin−/− mice. Our modeling shows that a similar elevation in βdark can fully explain the observed acceleration of flash response recovery in low Ca2+. Additionally, a reduction of the free Ca2+ in GCAPs−/− recoverin−/− rods shifted the inhibition constants of competitive PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) against the thermally activated and light-activated forms of PDE6 to opposite directions, indicating a complex interaction between IBMX, PDE6, and calcium. The discovered regulation of PDE6 is a previously unknown mechanism in the Ca2+-mediated modulation of rod light sensitivity.
Highlights
Phosphodiesterase-6 (PDE6) is a key protein in the G-protein cascade converting photon information to bioelectrical signals in vertebrate photoreceptor cells
We demonstrate that lowering of the extracellular calcium concentration reduces the light-sensitivity of rods by accelerating the photoresponse recovery in guanylate cyclase-activating proteins (GCAPs)−/− recoverin−/− background
We investigated the role of PDE6 in C a2+-dependent regulation of phototransduction in mammalian rods
Summary
Phosphodiesterase-6 (PDE6) is a key protein in the G-protein cascade converting photon information to bioelectrical signals in vertebrate photoreceptor cells. To broaden the operating range of photoreceptors, mammalian rod photoresponse recovery is accelerated mainly by two calcium sensor proteins: recoverin, modulating the lifetime of activated rhodopsin, and guanylate cyclase-activating proteins (GCAPs), regulating the cGMP synthesis. Our visual system can function in different illuminations covering a 1 012-fold range[6] This requires efficient light adaptation mechanisms in various levels of visual perception, which in the photoreceptor level are mostly mediated by controlling intracellular C a2+ concentration. PDE6 activation causes a rapid drop in the cGMP concentration, leading to the closure of cyclic nucleotide-gated (CNG) channels in the rod outer segment plasma membrane, reduction of the circulating “light-sensitive” current, and hyperpolarization of the cell (for reviews, see, e.g.8,9). We, together with others, demonstrated that in addition to GCAPs and recoverin, there exists an unknown calcium-mediated light adaptation mechanism in mouse rods[16]
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