title: Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297.
abstract: 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.
authors.affiliation: Departments of Pharmacology and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wydeven
authors.affiliation: Departments of Pharmacology and.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Marron Fernandez de Velasco
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Yu
authors.initials: Y
authors.lastname: Du
authors.affiliation: Neuroscience, University of Minnesota, Minneapolis, MN 55455; and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Benneyworth
authors.affiliation: Neuroscience, University of Minnesota, Minneapolis, MN 55455; and.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Hearing
authors.affiliation: Neuroscience, University of Minnesota, Minneapolis, MN 55455; and.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Fischer
authors.affiliation: Neuroscience, University of Minnesota, Minneapolis, MN 55455; and.
authors.forename: Mark John
authors.initials: MJ
authors.lastname: Thomas
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232 wickm002@umn.edu david.weaver@vanderbilt.edu.
authors.forename: C David
authors.initials: CD
authors.lastname: Weaver
authors.affiliation: Departments of Pharmacology and wickm002@umn.edu david.weaver@vanderbilt.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D015640:Ion Channel Gating / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*
chemical_list: D014151:Anti-Anxiety Agents; C587714:CID 56642816; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D010671:Phenylurea Compounds; D011720:Pyrazoles; D001418:Baclofen
keywords: electrophysiology; structure–activity relationship