Regulation of the Kv2.1 potassium channel by MinK and MiRP1.
Kv2.1 is a voltage-gated potassium (Kv) channel alpha-subunit expressed in mammalian heart and brain. MinK-related peptides (MiRPs), encoded by KCNE genes, are single-transmembrane domain ancillary subunits that form complexes with Kv channel alpha-subunits to modify their function. Mutations in human MinK (KCNE1) and MiRP1 (KCNE2) are associated with inherited and acquired forms of long QT syndrome (LQTS). Here, coimmunoprecipitations from rat heart tissue suggested that both MinK and MiRP1 form native cardiac complexes with Kv2.1. In whole-cell voltage-clamp studies of subunits expressed in CHO cells, rat MinK and MiRP1 reduced Kv2.1 current density three- and twofold, respectively; slowed Kv2.1 activation (at +60 mV) two- and threefold, respectively; and slowed Kv2.1 deactivation less than twofold. Human MinK slowed Kv2.1 activation 25%, while human MiRP1 slowed Kv2.1 activation and deactivation twofold. Inherited mutations in human MinK and MiRP1, previously associated with LQTS, were also evaluated. D76N-MinK and S74L-MinK reduced Kv2.1 current density (threefold and 40%, respectively) and slowed deactivation (60% and 80%, respectively). Compared to wild-type human MiRP1-Kv2.1 complexes, channels formed with M54T- or I57T-MiRP1 showed greatly slowed activation (tenfold and fivefold, respectively). The data broaden the potential roles of MinK and MiRP1 in cardiac physiology and support the possibility that inherited mutations in either subunit could contribute to cardiac arrhythmia by multiple mechanisms.
McCrossan
Zoe A
ZA
Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
Roepke
Torsten K
TK
Lewis
Anthony
A
Panaghie
Gianina
G
Abbott
Geoffrey W
GW
D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004594:Electrophysiology; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051669:Shab Potassium Channels / Q000235:genetics / Q000378:metabolism*
C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C484268:Kcne1 protein, rat; D024642:Potassium Channels, Voltage-Gated; D051669:Shab Potassium Channels