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- Title
K<sup>+</sup> Channel Regulator KCR1 Suppresses Heart Rhythm by Modulating the Pacemaker Current I<sub>f</sub>.
- Authors
Michels, Guido; Er, Fikret; Khan, Ismail F.; Endres-Becker, Jeannette; Brandt, Mathias C.; Gassanov, Natig; Johns, David C.; Hoppe, Uta C.
- Abstract
Hyperpolarization-activated, cyclic nucleotide sensitive (HCN) channels underlie the pacemaker current If, which plays an essential role in spontaneous cardiac activity. HCN channel subunits (HCN1-4) are believed to be modulated by additional regulatory proteins, which still have to be identified. Using biochemistry, molecularbiology and electrophysiology methods we demonstrate a protein-protein interaction between HCN2 and the K+ channel regulator protein 1, named KCR1. In coimmunoprecipitation experiments we show that KCR1 and HCN2 proteins are able to associate. Heterologously expressed HCN2 whole-cell current density was significantly decreased by KCR1. KCR1 profoundly suppressed IHCN2 single-channel activity, indicating a functional interaction between KCR1 and the HCN2 channel subunit. Endogenous KCR1 expression could be detected in adult and neonatal rat ventriculocytes. Adenoviral-mediated overexpression of KCR1 in rat cardiomyocytes (i) reduced If whole-cell currents, (ii) suppressed most single-channel gating parameters, (iii) altered the activation kinetics, (iv) suppressed spontaneous action potential activity, and (v) the beating rate. More importantly, siRNA-based knock-down of endogenous KCR1 increased the native If current size and single-channel activity and accelerated spontaneous beating rate, supporting an inhibitory action of endogenous KCR1 on native If. Our observations demonstrate for the first time that KCR1 modulates IHCN2/If channel gating and indicate that KCR1 serves as a regulator of cardiac automaticity.
- Subjects
PACEMAKER cells; GENETICS of biological rhythms; SEXUAL cycle; CELL cycle; CYCLIC nucleotides; NUCLEOTIDE analysis; BIOCHEMISTRY; BIOCHEMICAL genetics; CHEMICAL biology
- Publication
PLoS ONE, 2008, Vol 3, Issue 1, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0001511