Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine

Addictive drugs, such as opioids, ethanol, cocaine, amphetamine, and phencyclidine (PCP), affect many functions of the nervous system and peripheral organs, resulting in severe health problems. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neur...

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Main Authors:	Kobayashi, Toru, Nishizawa, Daisuke, Ikeda, Kazutaka
Format:	Online
Language:	English
Published:	Bentham Science Publishers Ltd 2011
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137191/

id	pubmed-3137191
recordtype	oai_dc
spelling	pubmed-31371912011-09-01 Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine Kobayashi, Toru Nishizawa, Daisuke Ikeda, Kazutaka Article Addictive drugs, such as opioids, ethanol, cocaine, amphetamine, and phencyclidine (PCP), affect many functions of the nervous system and peripheral organs, resulting in severe health problems. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability through activation of various Gi/o protein-coupled receptors including opioid and CB1 cannabinoid receptors. Furthermore, the channels are directly activated by ethanol and inhibited by cocaine at toxic levels, but not affected by methylphenidate, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) at toxic levels. The primary pharmacological action of PCP is blockade of N-methyl-D-aspartate (NMDA) receptor channels that are associated with its psychotomimetic effects. PCP also interacts with several receptors and channels at relatively high concentrations. However, the molecular mechanisms underlying the various effects of PCP remain to be clarified. Here, we investigated the effects of PCP on GIRK channels using the Xenopus oocyte expression system. PCP weakly but significantly inhibited GIRK channels at micromolar concentrations, but not Kir1.1 and Kir2.1 channels. The PCP concentrations effective in inhibiting GIRK channels overlap clinically relevant brain concentrations in severe intoxication. The results suggest that partial inhibition of GIRK channels by PCP may contribute to some of the toxic effects after overdose. Bentham Science Publishers Ltd 2011-03 /pmc/articles/PMC3137191/ /pubmed/21886598 http://dx.doi.org/10.2174/157015911795017407 Text en ©2011 Bentham Science Publishers Ltd. http://creativecommons.org/licenses/by/2.5/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kobayashi, Toru Nishizawa, Daisuke Ikeda, Kazutaka
spellingShingle	Kobayashi, Toru Nishizawa, Daisuke Ikeda, Kazutaka Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine
author_facet	Kobayashi, Toru Nishizawa, Daisuke Ikeda, Kazutaka
author_sort	Kobayashi, Toru
title	Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine
title_short	Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine
title_full	Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine
title_fullStr	Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine
title_full_unstemmed	Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine
title_sort	inhibition of g protein-activated inwardly rectifying k+ channels by phencyclidine
description	Addictive drugs, such as opioids, ethanol, cocaine, amphetamine, and phencyclidine (PCP), affect many functions of the nervous system and peripheral organs, resulting in severe health problems. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability through activation of various Gi/o protein-coupled receptors including opioid and CB1 cannabinoid receptors. Furthermore, the channels are directly activated by ethanol and inhibited by cocaine at toxic levels, but not affected by methylphenidate, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) at toxic levels. The primary pharmacological action of PCP is blockade of N-methyl-D-aspartate (NMDA) receptor channels that are associated with its psychotomimetic effects. PCP also interacts with several receptors and channels at relatively high concentrations. However, the molecular mechanisms underlying the various effects of PCP remain to be clarified. Here, we investigated the effects of PCP on GIRK channels using the Xenopus oocyte expression system. PCP weakly but significantly inhibited GIRK channels at micromolar concentrations, but not Kir1.1 and Kir2.1 channels. The PCP concentrations effective in inhibiting GIRK channels overlap clinically relevant brain concentrations in severe intoxication. The results suggest that partial inhibition of GIRK channels by PCP may contribute to some of the toxic effects after overdose.
publisher	Bentham Science Publishers Ltd
publishDate	2011
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137191/
_version_	1611465735560757248

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Phencyclidine

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