TY - JOUR
T1 - Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297
AU - Wydeven, Nicole
AU - Marron Fernandez De Velasco, Ezequiel
AU - Du, Yu
AU - Benneyworth, Michael A.
AU - Hearing, Matthew C.
AU - Fischer, Rachel A.
AU - Thomas, Mark John
AU - Weaver, C. David
AU - Wickman, Kevin
PY - 2014/7/22
Y1 - 2014/7/22
N2 - 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.
AB - 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.
KW - Electrophysiology
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=84904607104&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84904607104&partnerID=8YFLogxK
U2 - 10.1073/pnas.1405190111
DO - 10.1073/pnas.1405190111
M3 - Article
C2 - 25002517
AN - SCOPUS:84904607104
SN - 0027-8424
VL - 111
SP - 10755
EP - 10760
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 29
ER -