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

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 βdarkcan 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.

Astrocytic Calcium and cAMP in Neurodegenerative Diseases

“…Both cAMP and cGMP degradation may be driven by a large group of phosphodiesterases (PDEs) classified into 11 families, some of which are regulated by Ca 2+ or Ca 2+ /CaM (Bender and Beavo, 2006 ; Tenner et al, 2020 ; Turunen and Koskelainen, 2021 ). Given that most of tmAC isoforms, PKA and cyclic nucleotide phosphodiesterases (PDEs), may be located at the scaffold protein complexes called A-kinase anchoring proteins (AKAPs), it is plausible that the spatial and temporal organization of AKAPs orchestrates synthesis and degradation of the second messenger at the specific subcellular sites.…”

The dynamic landscape of chromatin accessibility and active regulatory elements in the mediobasal hypothalamus influences the seasonal activation of the reproductive axis in the male quail under long light exposure

“…In addition to genes associated with classic retinoic acid signaling, genes associated with gained chromatin opening were significantly enriched in pathways related to GTPase-mediated signal transduction. Small GTPases usually act as a molecular switches in regulating signal transduction [ 58 ] In the visual system, cGMP is the main intracellular messenger that converts light stimuli into electrical responses, and the balance of cGMP is regulated by the photoreceptor phosphodiesterase PDE6 [ 59 ], Activated PDE6 can mediate the closure of cyclic nucleotide-gated channels (CNG channels) by hydrolyzing cGMP, thus enabling the transmission of optical signals [ 60 ]. In addition, the transcriptional activity of PDE6H is regulated by T3 by binding to the TRs [ 7 , 61 , 62 ].…”

Structural basis of calmodulin modulation of the rod cyclic nucleotide-gated channel

“…Ca 2+ plays a fundamental role in rod photoreceptors: It terminates the light response, adjusts light sensitivity, and restores the dark state. Ca 2+ controls several enzymes of the phototransduction cascade via small Ca 2+ -binding proteins ( 7 – 15 ). One of these regulatory proteins is calmodulin (CaM), which lowers the open probability of the CNG channel ( 16 – 19 ).…”