title: Mechanisms of Calmodulin Regulation of Different Isoforms of Kv7.4 K+ Channels.
abstract: Calmodulin (CaM), a Ca(2+)-sensing protein, is constitutively bound to IQ domains of the C termini of human Kv7 (hKv7, KCNQ) channels to mediate Ca(2+)-dependent reduction of Kv7 currents. However, the mechanism remains unclear. We report that CaM binds to two isoforms of the hKv7.4 channel in a Ca(2+)-independent manner but that only the long isoform (hKv7.4a) is regulated by Ca(2+)/CaM. Ca(2+)/CaM mediate reduction of the hKv7.4a channel by decreasing the channel open probability and altering activation kinetics. We took advantage of a known missense mutation (G321S) that has been linked to progressive hearing loss to further examine the inhibitory effects of Ca(2+)/CaM on the Kv7.4 channel. Using multidisciplinary techniques, we demonstrate that the G321S mutation may destabilize CaM binding, leading to a decrease in the inhibitory effects of Ca(2+) on the channels. Our study utilizes an expression system to dissect the biophysical properties of the WT and mutant Kv7.4 channels. This report provides mechanistic insights into the critical roles of Ca(2+)/CaM regulation of the Kv7.4 channel under physiological and pathological conditions.
authors.affiliation: From the Department of Physiology and Cell Biology, Program in Communication Science, School of Medicine, University of Nevada, Reno, Reno, Nevada 85997.
authors.forename: Choong-Ryoul
authors.initials: CR
authors.lastname: Sihn
authors.affiliation: the Department of Internal Medicine, Division of Cardiovascular Medicine.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: the Department of Internal Medicine, Division of Cardiovascular Medicine.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Woltz
authors.affiliation: Department of Physiology and Membrane Biology, and the Northern California Health Care System, Department of Veterans Affairs, Mather, California 95655, and.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, California 95616.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Yang
authors.affiliation: the Department of Engineering Technology, College of Science and Technology, Tarleton State University, Stephenville, Texas 76402.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, University of California, Davis, Davis, California 95616.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
authors.affiliation: the Department of Internal Medicine, Division of Cardiovascular Medicine, the Northern California Health Care System, Department of Veterans Affairs, Mather, California 95655, and.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: the Department of Internal Medicine, Division of Cardiovascular Medicine, the Northern California Health Care System, Department of Veterans Affairs, Mather, California 95655, and.
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
authors.affiliation: From the Department of Physiology and Cell Biology, Program in Communication Science, School of Medicine, University of Nevada, Reno, Reno, Nevada 85997, enyamoah@gmail.com.
authors.forename: Ebenezer N
authors.initials: EN
authors.lastname: Yamoah
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002118:Calcium / Q000737:chemistry; D002147:Calmodulin / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D004594:Electrophysiology; D000939:Epitopes / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D007477:Ions; D051656:KCNQ Potassium Channels / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry; D017386:Sequence Homology, Amino Acid
chemical_list: D002147:Calmodulin; D000939:Epitopes; D007477:Ions; D051656:KCNQ Potassium Channels; C117367:KCNQ4 protein, human; D020033:Protein Isoforms; D002118:Calcium
keywords: calcium; calmodulin (CaM); hearing; ion channel; potassium channel