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Originally published In Press as doi:10.1074/jbc.M100830200 on April 27, 2001

J. Biol. Chem., Vol. 276, Issue 31, 29233-29241, August 3, 2001
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Hyperpolarization-activated Cyclic Nucleotide-gated Channel 1 Is a Molecular Determinant of the Cardiac Pacemaker Current If*

Anna MoroniDagger §, Luisa Gorza||, Monica Beltrame**, Biagio GravanteDagger , Thomas Vaccari**, Marco E. BianchiDagger Dagger , Claudia AltomareDagger , Renato Longhi§§, Catherine Heurteaux¶¶, Maurizio Vitadello||, Antonio MalgaroliDagger Dagger , and Dario DiFrancescoDagger

From the Dagger  Dipartimento di Fisiologia e Biochimica Generali, the § Dipartimento di Biologia, and the ** Dipartimento di Genetica e di Biologia dei Microrganismi, Università degli Studi di Milano, via Celoria 26, Milano 20133, the || Consiglio Nazionale delle Ricerche (CNR), Centro di Studio per la Biologia e Fisiopatologia Muscolare and Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, via Trieste 75, Padova 35121, the Dagger Dagger  Dipartimento Ricerca Scientifica e Tecnologica (DIBIT), Istituto Scientifico San Raffaele (HSR), 20123 Milano, §§ CNR, Istituto di Biocatalisi e Riconoscimento Molecolare, via M. Bianco 9, Milano 20131, Italy, and the ¶¶ Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia Antipolis, 660 route des Lucioles, Sophia Antipolis, Valbonne 06560, France

The pacemaker current If of the sinoatrial node (SAN) is a major determinant of cardiac diastolic depolarization and plays a key role in controlling heart rate and its modulation by neurotransmitters. Substantial expression of two different mRNAs (HCN4, HCN1) of the family of pacemaker channels (HCN) is found in rabbit SAN, suggesting that the native channels may be formed by different isoforms. Here we report the cloning and heterologous expression of HCN1 from rabbit SAN and its specific localization in pacemaker myocytes. rbHCN1 is an 822-amino acid protein that, in human embryonic kidney 293 cells, displayed electrophysiological properties similar to those of If, suggesting that HCN1 can form a pacemaker channel. The presence of HCN1 in the SAN myocytes but not in nearby heart regions, and the electrophysiological properties of the channels formed by it, suggest that HCN1 plays a central and specific role in the formation of SAN pacemaker currents.

* This work was supported by MURST and COFIN 1999 and 2000 grants (to A. Mo., L. G., and D. D.), Consiglio Nazionale delle Ricerche Grant 98.03045.CT04 (to L. G.), Giunta RegioneVeneto-Ricerca sanitaria finalizzata Grant 758/01/97 (to L. G.), INFM (to D. D.), and Telethon Grant 971 (to D. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

 The nucleotide sequence reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number AF168122 (rbHCN1).

To whom correspondence should be addressed: Dipartimento di Fisiologia e Biochimica Generali, Sezione di Fisiologia Molecolare e Neurobiologia, via Celoria 26, Milano 20133, Italy. E-mail: anna.moroni@unimi.it.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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