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...

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Autores principales:	Teemu Turunen, Ari Koskelainen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a800473aa0b54762bc540317f671c048
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spelling	oai:doaj.org-article:a800473aa0b54762bc540317f671c0482021-12-02T14:53:42ZFunctional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors10.1038/s41598-021-88140-82045-2322https://doaj.org/article/a800473aa0b54762bc540317f671c0482021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88140-8https://doaj.org/toc/2045-2322Abstract 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 (β dark ) 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 β 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.Teemu TurunenAri KoskelainenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Teemu Turunen Ari Koskelainen Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors
description	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 (β dark ) 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 β 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.
format	article
author	Teemu Turunen Ari Koskelainen
author_facet	Teemu Turunen Ari Koskelainen
author_sort	Teemu Turunen
title	Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors
title_short	Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors
title_full	Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors
title_fullStr	Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors
title_full_unstemmed	Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors
title_sort	functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a800473aa0b54762bc540317f671c048
work_keys_str_mv	AT teemuturunen functionalmodulationofphosphodiesterase6bycalciuminmouserodphotoreceptors AT arikoskelainen functionalmodulationofphosphodiesterase6bycalciuminmouserodphotoreceptors
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Functional modulation of phosphodiesterase-6 by calcium in mouse rod photoreceptors

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