Mechanisms of calmodulin regulation of different isoforms of Kv7.4 K+ channels

Choong Ryoul Sihn, Hyo Jeong Kim, Ryan L. Woltz, Vladimir Yarov-Yarovoy, Pei Chi Yang, Jun Xu, Colleen E. Clancy, Xiao Dong Zhang, Nipavan Chiamvimonvat, Ebenezer N. Yamoah

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Calmodulin (CaM), a Ca2+-sensing protein, is constitutively bound to IQ domains of the C termini of human Kv7 (hKv7, KCNQ) channels to mediate Ca2+-dependent reduction of Kv7 currents. However, the mechanism remains unclear. We report thatCaMbinds to two isoforms of the hKv7.4 channel in a Ca2+- independent manner but that only the long isoform (hKv7.4a) is regulated by Ca2+/CaM. Ca2+/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 Ca2+/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 Ca2+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 Ca2+/CaM regulation of the Kv7.4 channel under physiological and pathological conditions.

Original languageEnglish (US)
Pages (from-to)2499-2509
Number of pages11
JournalJournal of Biological Chemistry
Volume291
Issue number5
DOIs
StatePublished - Jan 29 2016

Fingerprint

Calmodulin
Protein Isoforms
Audition
Missense Mutation
Hearing Loss
Chemical activation
Mutation
Kinetics
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mechanisms of calmodulin regulation of different isoforms of Kv7.4 K+ channels. / Sihn, Choong Ryoul; Kim, Hyo Jeong; Woltz, Ryan L.; Yarov-Yarovoy, Vladimir; Yang, Pei Chi; Xu, Jun; Clancy, Colleen E.; Zhang, Xiao Dong; Chiamvimonvat, Nipavan; Yamoah, Ebenezer N.

In: Journal of Biological Chemistry, Vol. 291, No. 5, 29.01.2016, p. 2499-2509.

Research output: Contribution to journalArticle

Sihn, Choong Ryoul ; Kim, Hyo Jeong ; Woltz, Ryan L. ; Yarov-Yarovoy, Vladimir ; Yang, Pei Chi ; Xu, Jun ; Clancy, Colleen E. ; Zhang, Xiao Dong ; Chiamvimonvat, Nipavan ; Yamoah, Ebenezer N. / Mechanisms of calmodulin regulation of different isoforms of Kv7.4 K+ channels. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 5. pp. 2499-2509.
@article{30f5b4ddabe2497a8426d45f4154881a,
title = "Mechanisms of calmodulin regulation of different isoforms of Kv7.4 K+ channels",
abstract = "Calmodulin (CaM), a Ca2+-sensing protein, is constitutively bound to IQ domains of the C termini of human Kv7 (hKv7, KCNQ) channels to mediate Ca2+-dependent reduction of Kv7 currents. However, the mechanism remains unclear. We report thatCaMbinds to two isoforms of the hKv7.4 channel in a Ca2+- independent manner but that only the long isoform (hKv7.4a) is regulated by Ca2+/CaM. Ca2+/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 Ca2+/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 Ca2+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 Ca2+/CaM regulation of the Kv7.4 channel under physiological and pathological conditions.",
author = "Sihn, {Choong Ryoul} and Kim, {Hyo Jeong} and Woltz, {Ryan L.} and Vladimir Yarov-Yarovoy and Yang, {Pei Chi} and Jun Xu and Clancy, {Colleen E.} and Zhang, {Xiao Dong} and Nipavan Chiamvimonvat and Yamoah, {Ebenezer N.}",
year = "2016",
month = "1",
day = "29",
doi = "10.1074/jbc.M115.668236",
language = "English (US)",
volume = "291",
pages = "2499--2509",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "5",

}

TY - JOUR

T1 - Mechanisms of calmodulin regulation of different isoforms of Kv7.4 K+ channels

AU - Sihn, Choong Ryoul

AU - Kim, Hyo Jeong

AU - Woltz, Ryan L.

AU - Yarov-Yarovoy, Vladimir

AU - Yang, Pei Chi

AU - Xu, Jun

AU - Clancy, Colleen E.

AU - Zhang, Xiao Dong

AU - Chiamvimonvat, Nipavan

AU - Yamoah, Ebenezer N.

PY - 2016/1/29

Y1 - 2016/1/29

N2 - Calmodulin (CaM), a Ca2+-sensing protein, is constitutively bound to IQ domains of the C termini of human Kv7 (hKv7, KCNQ) channels to mediate Ca2+-dependent reduction of Kv7 currents. However, the mechanism remains unclear. We report thatCaMbinds to two isoforms of the hKv7.4 channel in a Ca2+- independent manner but that only the long isoform (hKv7.4a) is regulated by Ca2+/CaM. Ca2+/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 Ca2+/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 Ca2+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 Ca2+/CaM regulation of the Kv7.4 channel under physiological and pathological conditions.

AB - Calmodulin (CaM), a Ca2+-sensing protein, is constitutively bound to IQ domains of the C termini of human Kv7 (hKv7, KCNQ) channels to mediate Ca2+-dependent reduction of Kv7 currents. However, the mechanism remains unclear. We report thatCaMbinds to two isoforms of the hKv7.4 channel in a Ca2+- independent manner but that only the long isoform (hKv7.4a) is regulated by Ca2+/CaM. Ca2+/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 Ca2+/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 Ca2+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 Ca2+/CaM regulation of the Kv7.4 channel under physiological and pathological conditions.

UR - http://www.scopus.com/inward/record.url?scp=84956760942&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84956760942&partnerID=8YFLogxK

U2 - 10.1074/jbc.M115.668236

DO - 10.1074/jbc.M115.668236

M3 - Article

C2 - 26515070

AN - SCOPUS:84956760942

VL - 291

SP - 2499

EP - 2509

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 5

ER -