Inhibition of g protein-activated inwardly rectifying k channels by phencyclidine.
Toru Kobayashi, Daisuke Nishizawa, Kazutaka Ikeda
Current Neuropharmacology March 2011 DOI: 10.2174/157015911795017407 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Basic experimental study using Xenopus oocyte expression system Peer reviewed |
|---|---|
| Population | Xenopus oocytes expressing GIRK, Kir1.1, and Kir2.1 channels |
| Intervention | Phencyclidine (PCP) |
| Keywords | Girk channel Kir channel Phencyclidine Xenopus oocyte. Intoxication |
| Key findings | PCP weakly but significantly inhibited GIRK channels at micromolar concentrations, but did not affect Kir1.1 or Kir2.1 channels. The effective concentrations overlap with clinically relevant brain concentrations in severe intoxication, suggesting that partial GIRK channel inhibition may contribute to toxic effects after overdose. |
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.