The impact of ancillary subunits on small-molecule interactions with voltage-gated potassium channels.
Voltage-gated potassium channels (Kv channels) are the major determinants of cellular repolarization in excitable cells--they open in response to depolarization and facilitate selective efflux of potassium ions across the plasma membrane. Because of the importance of exquisitely timed cellular repolarization in controlling action potential morphology and duration, Kv channels are attractive therapeutic targets, particularly for drugs aimed at controlling aberrant electrical excitability such as is observed in cardiac arrhythmia and epilepsy. While the pore-forming alpha subunits of Kv channels are sufficient to form functional channels, a host of cytoplasmic and transmembrane ancillary subunits modulate their trafficking, function and regulation in vivo. Here, we consider the impact of ancillary subunits on Kv channel pharmacology, and discuss how increased understanding of the roles of ancillary subunits in native Kv channel complexes will lead to development of safer, more specific and more efficacious therapeutic small molecules.
Panaghie
Gianina
G
Greenberg Division of Cardiology, Department of Medicine, Cornell University, Weill Medical College, 520 East 70th Street, New York, NY 10021, USA.
Abbott
Geoffrey W
GW
D000818:Animals; D006321:Heart / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D051605:Kv Channel-Interacting Proteins / Q000737:chemistry / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits; D019789:Tetraethylammonium / Q000494:pharmacology
C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; D051657:KCNQ1 Potassium Channel; D051605:Kv Channel-Interacting Proteins; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits; D019789:Tetraethylammonium; D011188:Potassium