Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297

Nicole Wydeven, Ezequiel Marron Fernandez De Velasco, Yu Du, Michael A. Benneyworth, Matthew C. Hearing, Rachel A. Fischer, Mark John Thomas, C. David Weaver, Kevin Wickman

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


ML297 was recently identified as a potent and selective small molecule agonist of G-protein-gated inwardly rectifying K+ (GIRK/Kir3) channels. Here, we show ML297 selectively activates recombinant neuronal GIRK channels containing the GIRK1 subunit in a manner that requires phosphatidylinositol-4,5-bisphosphate (PIP2), but is otherwise distinct from receptor-induced, G-protein-dependent channel activation. Two amino acids unique to the pore helix (F137) and second membrane-spanning (D173) domain of GIRK1 were identified as necessary and sufficient for the selective activation of GIRK channels by ML297. Further investigation into the behavioral effects of ML297 revealed that in addition to its known antiseizure efficacy, ML297 decreases anxiety-related behavior without sedative or addictive liabilities. Importantly, the anxiolytic effect of ML297 was lost in mice lacking GIRK1. Thus, activation of GIRK1-containing channels by ML297 or derivatives may represent a new approach to the treatment of seizure and/or anxiety disorders.

Original languageEnglish (US)
Pages (from-to)10755-10760
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number29
StatePublished - Jul 22 2014


  • Electrophysiology
  • Structure-activity relationship


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