GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders

Abstract

Substance use disorders (SUDs) are chronic, lifelong disorders that have serious consequences. Repeated substance use alters brain function. G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed widely in the brain, including the reward system, and regulate neuronal excitability. Functional GIRK channels are identified as heterotetramers of GIRK subunits (GIRK1–4). The GIRK1, GIRK2, and GIRK3 subunits are mainly expressed in rodent brain regions, and various addictive substances act on the brain through GIRK channels. Studies with animals (knockout and missense mutation animals) and humans have demonstrated the involvement of GIRK channels in the effects of addictive substances. Additionally, GIRK channel blockers affect behavioral responses to addictive substances. Thus, GIRK channels play a key role in SUDs, and GIRK channel modulators may be candidate medications. Ifenprodil is a GIRK channel blocker that does not have serious side effects. Two clinical trials were conducted to investigate the effects of ifenprodil in patients with alcohol or methamphetamine use disorder. Although the number of participants was relatively low, evidence of its safety and efficacy was found. The present review discusses the potential of GIRK channel modulators as possible medications for addiction. Therapeutic agents that target GIRK channels may be promising for the treatment of SUDs.

Structural determinants of the direct inhibition of GIRK channels by Sigma-1 receptor antagonist

“…Previously, a possible usage of BD1047 was suggested in alcohol use disorder, because BD1047 could attenuate ethanol-induced intracellular Ca 2+ in rat hippocampus through the modulation of the function of S1R and ER-bound IP 3 ( 27 ). It is known that GIRK channels can be activated by alcohol ( 6 ) and the usage of GIRK inhibitors such as ifenprodil could block the alcohol-induced GIRK currents ( 37 ). Thus, it is possible that BD1047 might play a therapeutic role in the alcohol use disorder also by inhibiting GIRK currents, besides the inhibition of the function of S1R.…”