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 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.
Highlights
G protein-activated inwardly rectifying K+ (GIRK) channels are members of a family of inwardly rectifying K+ (Kir) channels that includes seven subfamilies [1]
Neuronal GIRK channels are predominantly heteromultimers composed of GIRK1 and GIRK2 subunits in most brain regions or homomultimers composed of GIRK2 subunits in the substantia nigra, whereas atrial GIRK channels are heteromultimers composed of GIRK1 and GIRK4 subunits [2]
Methylphenidate, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) at toxic levels had little effect on GIRK channels, these drugs at higher concentrations inhibited the channels to a lesser extent than cocaine [12]
Summary
G protein-activated inwardly rectifying K+ (GIRK) channels ( known as Kir channels) are members of a family of inwardly rectifying K+ (Kir) channels that includes seven subfamilies [1]. Four GIRK channel subunits have been identified in mammals [1]. Neuronal GIRK channels are predominantly heteromultimers composed of GIRK1 and GIRK2 subunits in most brain regions or homomultimers composed of GIRK2 subunits in the substantia nigra, whereas atrial GIRK channels are heteromultimers composed of GIRK1 and GIRK4 subunits [2]. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and heart rate through activation of various Gi/o protein-coupled receptors, such as opioid, CB1 cannabinoid, and D2 dopamine receptors [2]. We demonstrated that cocaine at toxic levels inhibited GIRK channels expressed in Xenopus oocytes. Methylphenidate, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) at toxic levels had little effect on GIRK channels, these drugs at higher concentrations inhibited the channels to a lesser extent than cocaine [12]
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