KCNE variants reveal a critical role of the beta subunit carboxyl terminus in PKA-dependent regulation of the IKs potassium channel.
Co-assembly of KCNQ1 with different accessory, or beta, subunits that are members of the KCNE family results in potassium (K+) channels that conduct functionally distinct currents. The alpha subunit KCNQ1 conducts a slowly activated delayed rectifier K+ current (IKs), a major contributor to cardiac repolarization, when co-assembled with KCNE1 and channels that favor the open state when co-assembled with either KCNE2 or KCNE3. In the heart, stimulation of the sympathetic nervous system enhances IKs. A macromolecular signaling complex of the IKs channel including the targeting protein Yotiao coordinates up or downregulation of channel activity by protein kinase A (PKA) phosphorylation and dephosphorylation of molecules in the complex. beta-adrenergic receptor mediated IKs upregulation, a functional consequence of PKA phosphorylation of the KCNQ1 amino terminus (N-T), requires co-expression of KCNQ1/Yotiao with KCNE1. Here, we report that co-expression of KCNE2, like KCNE1, confers a functional channel response to KCNQ1 phosphorylation, but co-expression of KCNE3 does not. Amino acid sequence comparison among the KCNE peptides, and KCNE1 truncation experiments, reveal a segment of the predicted intracellular KCNE1 carboxyl terminus (C-T) that is necessary for functional transduction of PKA phosphorylated KCNQ1. Moreover, chimera analysis reveals a region of KCNE1 sufficient to confer cAMP-dependent functional regulation upon the KCNQ1_KCNE3_Yotiao channel. The property of specific beta subunits to transduce post-translational regulation of alpha subunits of ion channels adds another dimension to our understanding molecular mechanisms underlying the diversity of regulation of native K+ channels.
Kurokawa
Junko
J
Department of Bio-Informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan. junkokuro.bip@mri.tmd.ac.jp
Bankston
John R
JR
Kaihara
Asami
A
Chen
Lei
L
Furukawa
Tetsushi
T
Kass
Robert S
RS
D054758:A Kinase Anchor Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000378:metabolism*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014162:Transfection
D054758:A Kinase Anchor Proteins; C489619:KCNE2 protein, human; C418492:KCNE3 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D019319:Okadaic Acid; D000242:Cyclic AMP; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C463959:protein kinase A Calpha