Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol

Abstract Activation of G protein-gated inwardly rectifying potassium (GIRK) channels leads to a hyperpolarization of the neuron’s membrane potential, providing an important component of inhibition in the brain. In addition to the canonical G protein-activation pathway, GIRK channels are activated by...

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Autores principales:	Ian W. Glaaser, Paul A. Slesinger
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/110c715eac0a4b6084cf085de06f3e2f
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spelling	oai:doaj.org-article:110c715eac0a4b6084cf085de06f3e2f2021-12-02T15:05:46ZDual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol10.1038/s41598-017-04681-x2045-2322https://doaj.org/article/110c715eac0a4b6084cf085de06f3e2f2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04681-xhttps://doaj.org/toc/2045-2322Abstract Activation of G protein-gated inwardly rectifying potassium (GIRK) channels leads to a hyperpolarization of the neuron’s membrane potential, providing an important component of inhibition in the brain. In addition to the canonical G protein-activation pathway, GIRK channels are activated by small molecules but less is known about the underlying gating mechanisms. One drawback to previous studies has been the inability to control intrinsic and extrinsic factors. Here we used a reconstitution strategy with highly purified mammalian GIRK2 channels incorporated into liposomes and demonstrate that cholesterol or intoxicating concentrations of ethanol, i.e., >20 mM, each activate GIRK2 channels directly, in the absence of G proteins. Notably, both activators require the membrane phospholipid PIP2 but appear to interact independently with different regions of the channel. Elucidating the mechanisms underlying G protein-independent pathways of activating GIRK channels provides a unique strategy for developing new types of neuronal excitability modulators.Ian W. GlaaserPaul A. SlesingerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ian W. Glaaser Paul A. Slesinger Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol
description	Abstract Activation of G protein-gated inwardly rectifying potassium (GIRK) channels leads to a hyperpolarization of the neuron’s membrane potential, providing an important component of inhibition in the brain. In addition to the canonical G protein-activation pathway, GIRK channels are activated by small molecules but less is known about the underlying gating mechanisms. One drawback to previous studies has been the inability to control intrinsic and extrinsic factors. Here we used a reconstitution strategy with highly purified mammalian GIRK2 channels incorporated into liposomes and demonstrate that cholesterol or intoxicating concentrations of ethanol, i.e., >20 mM, each activate GIRK2 channels directly, in the absence of G proteins. Notably, both activators require the membrane phospholipid PIP2 but appear to interact independently with different regions of the channel. Elucidating the mechanisms underlying G protein-independent pathways of activating GIRK channels provides a unique strategy for developing new types of neuronal excitability modulators.
format	article
author	Ian W. Glaaser Paul A. Slesinger
author_facet	Ian W. Glaaser Paul A. Slesinger
author_sort	Ian W. Glaaser
title	Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol
title_short	Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol
title_full	Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol
title_fullStr	Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol
title_full_unstemmed	Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol
title_sort	dual activation of neuronal g protein-gated inwardly rectifying potassium (girk) channels by cholesterol and alcohol
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/110c715eac0a4b6084cf085de06f3e2f
work_keys_str_mv	AT ianwglaaser dualactivationofneuronalgproteingatedinwardlyrectifyingpotassiumgirkchannelsbycholesterolandalcohol AT paulaslesinger dualactivationofneuronalgproteingatedinwardlyrectifyingpotassiumgirkchannelsbycholesterolandalcohol
_version_	1718388688912646144

Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol

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