Modulators of G protein-activated inwardly rectifying K+ channels: potentially therapeutic agents for addictive drug users.
G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and heart rate through activation of various G protein-coupled receptors, such as opioid, cannabinoid, and D2 dopamine receptors. Therefore, modulators of GIRK channels may affect many brain functions. We have shown using Xenopus oocyte expression assays that ethanol directly activates GIRK channels, whereas various antipsychotics (thioridazine, clozapine, pimozide, and haloperidol) inhibit the channels. Here we investigated not only the effects of various selective serotonin reuptake inhibitor (SSRI) antidepressants (fluoxetine, citalopram, fluvoxamine, and zimelidine) and risperidone, an atypical antipsychotic, on GIRK channels, but also those of the various drugs tested on other Kir channels using the Xenopus oocyte system. Fluoxetine inhibited GIRK channels, whereas the other SSRIs and risperidone had a small or no effect on the channels. In contrast, Kir1.1 and Kir2.1 channels were insensitive to ethanol and various SSRIs and antipsychotics, although thioridazine weakly inhibited Kir1.1 channels. It has been shown that the function of GIRK channels is involved in seizure susceptibility, antinociception by opioids, cannabinoids, or ethanol, and cocaine reinforcement in studies using GIRK knockout mice and weaver mutant mice that have mutant GIRK2 channels insensitive to G proteins and ethanol. Activation of GIRK channels by opioids, cannabinoids, or ethanol may be one of these key effects. Therefore, GIRK channel modulators might be potential agents for the treatment of users of addictive drugs, such as cocaine, opioids, cannabinoids, and ethanol, as well as for the treatment of epilepsy and pain.
Kobayashi
Toru
T
Department of Molecular Neuropathology, Brain Research Institute, Niigata University, Niigata, Niigata 951-8585, Japan. torukoba@bri.niigata-u.ac.jp
Washiyama
Kazuo
K
Ikeda
Kazutaka
K
D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000188:drug therapy / Q000378:metabolism*; D014982:Xenopus laevis
D026902:Potassium Channel Blockers; D024661:Potassium Channels, Inwardly Rectifying; D019204:GTP-Binding Proteins