Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors

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 (beta(dark)) maximally by similar to 30% when recording local electroretinography across the rod outer segment layer from GCAPs(-/-) recoverin(-/-) mice. Our modeling shows that a similar elevation in beta(dark) 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.

Automated summary

The study reveals that phosphodiesterase-6 (PDE6) is regulated by calcium, playing a crucial role in converting photon information to bioelectrical signals in vertebrate photoreceptor cells. By decreasing rod intracellular Ca2+ concentration, the flash response recovery of photoreceptors can be accelerated, broadening their operating range and functionality.