C Terminus-mediated Control of Voltage and cAMP Gating of Hyperpolarization-activated Cyclic Nucleotide-gated Channels

Carlo Viscomi, Claudia Altomare, Annalisa Bucchi, Eva Camatini, Mirko Baruscotti, Anna Moroni, Dario DiFrancesco

Research output: Contribution to journalArticle

Abstract

The hyperpolarization-activated cyclic nucleotide-gated (HCN) family of "pacemaker" channels includes 4 isoforms, the kinetics and cAMP-induced modulation of which differ quantitatively. Because HCN isoforms are highly homologous in the central region, but diverge more substantially in the N and C termini, we asked whether these latter regions could contribute to the determination of channel properties. To this aim, we analyzed activation/deactivation kinetics and the response to cAMP of heterologously expressed isoforms mHCN1 and rbHCN4 and verified that mHCN1 has much faster kinetics and lower cAMP sensitivity than rbHCN4. We then constructed rbHCN4 chimeras by replacing either the N or the C terminus, or both, with the analogous domains from mHCN1. We found that: 1) replacement of the N terminus (chimera N1-4) did not substantially modify either the kinetics or cAMP dependence of wild-type channels; 2) replacement of the C terminus, on the contrary, resulted in a chimeric channel (4-C1), the kinetics of which were strongly accelerated compared with rbHCN4, and that was fully insensitive to cAMP; 3) replacement of both N and C termini led to the same results as replacement of the C terminus alone. These results indicate that the C terminus of rbHCN4 contributes to the regulation of voltage- and cAMP-dependent channel gating, possibly through interaction with other intracellular regions not belonging to the N terminus.

Original languageEnglish
Pages (from-to)29930-29934
Number of pages5
JournalJournal of Biological Chemistry
Volume276
Issue number32
DOIs
Publication statusPublished - Aug 10 2001

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Viscomi, C., Altomare, C., Bucchi, A., Camatini, E., Baruscotti, M., Moroni, A., & DiFrancesco, D. (2001). C Terminus-mediated Control of Voltage and cAMP Gating of Hyperpolarization-activated Cyclic Nucleotide-gated Channels. Journal of Biological Chemistry, 276(32), 29930-29934. https://doi.org/10.1074/jbc.M103971200