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The membrane protein MiRP3 regulates Kv4.2 channels in a KChIP‐dependent manner
Author(s) -
Levy Daniel I.,
Cepaitis Egle,
Wanderling Sherry,
Toth Peter T.,
Archer Stephen L.,
Goldstein Steve A. N.
Publication year - 2010
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2010.191395
Subject(s) - cytoplasm , myocyte , microbiology and biotechnology , protein subunit , membrane potential , biophysics , cardiac transient outward potassium current , patch clamp , voltage clamp , chemistry , immunofluorescence , depolarization , medicine , electrophysiology , biology , biochemistry , antibody , genetics , gene
MiRP3, the single‐span membrane protein encoded by KCNE4 , is localized by immunofluorescence microscopy to the transverse tubules of murine cardiac myocytes. MiRP3 is found to co‐localize with Kv4.2 subunits that contribute to cardiac transient outward potassium currents ( I to ). Whole‐cell, voltage‐clamp recordings of human MiRP3 and Kv4.2 expressed in a clonal cell line (tsA201) reveal MiRP3 to modulate Kv4.2 current activation, inactivation and recovery from inactivation. MiRP3 shifts the half‐maximal voltage for activation ( V 1/2 ) ∼20 mV and slows time to peak ∼100%. In addition, MiRP3 slows inactivation ∼100%, speeds recovery from inactivation ∼30%, and enhances restored currents so they ‘overshoot’ baseline levels. The cytoplasmic accessory subunit KChIP2 also assembles with Kv4.2 in tsA201 cells to increase peak current, shift V 1/2 ∼5 mV, slow time to peak ∼10%, slow inactivation ∼100%, and speed recovery from inactivation ∼250% without overshoot. Simultaneous expression of all three subunits yields a biophysical profile unlike either accessory subunit alone, abolishes MiRP3‐induced overshoot, and allows biochemical isolation of the ternary complex. Thus, regional heterogeneity in cardiac expression of MiRP3, Kv4.2 and KChIP2 in health and disease may establish the local attributes and magnitude of cardiac I to .