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Molecular mechanism of cAMP modulation of HCN pacemaker channels.
Nature. 2001 Jun 14; 411(6839):805-10.Nat

Abstract

Hyperpolarization-activated cation channels of the HCN gene family contribute to spontaneous rhythmic activity in both heart and brain. All four family members contain both a core transmembrane segment domain, homologous to the S1-S6 regions of voltage-gated K+ channels, and a carboxy-terminal 120 amino-acid cyclic nucleotide-binding domain (CNBD) motif. Homologous CNBDs are responsible for the direct activation of cyclic nucleotide-gated channels and for modulation of the HERG voltage-gated K+ channel--important for visual and olfactory signalling and for cardiac repolarization, respectively. The direct binding of cyclic AMP to the cytoplasmic site on HCN channels permits the channels to open more rapidly and completely after repolarization of the action potential, thereby accelerating rhythmogenesis. However, the mechanism by which cAMP binding modulates HCN channel gating and the basis for functional differences between HCN isoforms remain unknown. Here we demonstrate by constructing truncation mutants that the CNBD inhibits activation of the core transmembrane domain. cAMP binding relieves this inhibition. Differences in activation gating and extent of cAMP modulation between the HCN1 and HCN2 isoforms result largely from differences in the efficacy of CNBD inhibition.

Authors+Show Affiliations

Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11459060

Citation

Wainger, B J., et al. "Molecular Mechanism of cAMP Modulation of HCN Pacemaker Channels." Nature, vol. 411, no. 6839, 2001, pp. 805-10.
Wainger BJ, DeGennaro M, Santoro B, et al. Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature. 2001;411(6839):805-10.
Wainger, B. J., DeGennaro, M., Santoro, B., Siegelbaum, S. A., & Tibbs, G. R. (2001). Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature, 411(6839), 805-10.
Wainger BJ, et al. Molecular Mechanism of cAMP Modulation of HCN Pacemaker Channels. Nature. 2001 Jun 14;411(6839):805-10. PubMed PMID: 11459060.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular mechanism of cAMP modulation of HCN pacemaker channels. AU - Wainger,B J, AU - DeGennaro,M, AU - Santoro,B, AU - Siegelbaum,S A, AU - Tibbs,G R, PY - 2001/7/19/pubmed PY - 2001/8/10/medline PY - 2001/7/19/entrez SP - 805 EP - 10 JF - Nature JO - Nature VL - 411 IS - 6839 N2 - Hyperpolarization-activated cation channels of the HCN gene family contribute to spontaneous rhythmic activity in both heart and brain. All four family members contain both a core transmembrane segment domain, homologous to the S1-S6 regions of voltage-gated K+ channels, and a carboxy-terminal 120 amino-acid cyclic nucleotide-binding domain (CNBD) motif. Homologous CNBDs are responsible for the direct activation of cyclic nucleotide-gated channels and for modulation of the HERG voltage-gated K+ channel--important for visual and olfactory signalling and for cardiac repolarization, respectively. The direct binding of cyclic AMP to the cytoplasmic site on HCN channels permits the channels to open more rapidly and completely after repolarization of the action potential, thereby accelerating rhythmogenesis. However, the mechanism by which cAMP binding modulates HCN channel gating and the basis for functional differences between HCN isoforms remain unknown. Here we demonstrate by constructing truncation mutants that the CNBD inhibits activation of the core transmembrane domain. cAMP binding relieves this inhibition. Differences in activation gating and extent of cAMP modulation between the HCN1 and HCN2 isoforms result largely from differences in the efficacy of CNBD inhibition. SN - 0028-0836 UR - https://www.unboundmedicine.com/medline/citation/11459060/Molecular_mechanism_of_cAMP_modulation_of_HCN_pacemaker_channels_ L2 - https://doi.org/10.1038/35081088 DB - PRIME DP - Unbound Medicine ER -