Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Curr Neuropharmacol
2011 Mar 01;91:244-6. doi: 10.2174/157015911795017407.
Show Gene links
Show Anatomy links
Inhibition of g protein-activated inwardly rectifying k channels by phencyclidine.
Kobayashi T
,
Nishizawa D
,
Ikeda K
.
???displayArticle.abstract???
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 CB(1) 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.
Fig. (1). Inhibitory effects of PCP on GIRK channels expressed in Xenopus oocytes. (A) Top, in an oocyte injected with GIRK1 and GIRK2 mRNA, current responses to 10 µM and 100 µM PCP and to 3 mM Ba2+, a Kir channel blocker. Middle, in an oocyte injected with Kir1.1 mRNA, current responses to 100 µM PCP and to 3 mM Ba2+. Bottom, in an uninjected oocyte, no significant current responses to 100 µM PCP or 3 mM Ba2+. Asterisks show the zero current level. Bars show the duration of application. (B) Concentration-dependent inhibition of GIRK channels by PCP. The magnitudes of inhibition of GIRK currents by PCP were compared with the current components sensitive to 3 mM Ba2+.
Fig. (2). Comparison of the effects of five addictive drugs: PCP, cocaine, methylphenidate (MPH), methamphetamine (MAP) and MDMA, on GIRK channels. Drug concentration was 100 µM. The magnitudes of inhibition of GIRK currents by the drugs were compared with the 3 mM Ba2+-sensitive current components. Data except for PCP are from our previous study [12].
Bailey,
Phencyclidine abuse. Clinical findings and concentrations in biological fluids after nonfatal intoxication.
1979, Pubmed
Bailey,
Phencyclidine abuse. Clinical findings and concentrations in biological fluids after nonfatal intoxication.
1979,
Pubmed
Budd,
Phencyclidine concentrations in postmortem body fluids and tissues.
1982,
Pubmed
Evaul,
Testosterone and progesterone rapidly attenuate plasma membrane Gbetagamma-mediated signaling in Xenopus laevis oocytes by signaling through classical steroid receptors.
2007,
Pubmed
,
Xenbase
Ffrench-Mullen,
Phencyclidine block of calcium current in isolated guinea-pig hippocampal neurones.
1992,
Pubmed
Javitt,
Recent advances in the phencyclidine model of schizophrenia.
1991,
Pubmed
Kelly,
Estrogen modulation of K(+) channel activity in hypothalamic neurons involved in the control of the reproductive axis.
2002,
Pubmed
Kobayashi,
Ethanol opens G-protein-activated inwardly rectifying K+ channels.
1999,
Pubmed
,
Xenbase
Kobayashi,
G protein-activated inwardly rectifying potassium channels as potential therapeutic targets.
2006,
Pubmed
Kobayashi,
Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes.
2000,
Pubmed
,
Xenbase
Kobayashi,
Inhibition by cocaine of G protein-activated inwardly rectifying K+ channels expressed in Xenopus oocytes.
2007,
Pubmed
,
Xenbase
Kobayashi,
Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs.
2004,
Pubmed
,
Xenbase
Kobayashi,
Inhibition of G protein-activated inwardly rectifying K+ channels by fluoxetine (Prozac).
2003,
Pubmed
,
Xenbase
Kobayashi,
Inhibition of G protein-activated inwardly rectifying K+ channels by the antidepressant paroxetine.
2006,
Pubmed
,
Xenbase
Kokoz,
Anaesthetic phencyclidine, blocker of the ATP-sensitive potassium channels.
1994,
Pubmed
Kuzhikandathil,
Classic D1 dopamine receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) directly inhibits G protein-coupled inwardly rectifying potassium channels.
2002,
Pubmed
Liden,
Phencyclidine. Nine cases of poisoning.
1975,
Pubmed
Proksch,
The effect of rate of drug administration on the extent and time course of phencyclidine distribution in rat brain, testis, and serum.
2000,
Pubmed
Reimann,
Inwardly rectifying potassium channels.
1999,
Pubmed
Signorini,
Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2.
1997,
Pubmed
Yamakura,
Differential effects of general anesthetics on G protein-coupled inwardly rectifying and other potassium channels.
2001,
Pubmed
,
Xenbase
Zhou,
Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels.
2001,
Pubmed
,
Xenbase
