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J. Biol. Chem., Vol. 279, Issue 42, 43847-43853, October 15, 2004

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Interaction of the Pacemaker Channel HCN1 with Filamin A^*

Biagio Gravante, Andrea Barbuti, Raffaella Milanesi, Ivan Zappi, Carlo Viscomi, and Dario DiFrancesco¶

From the Department of Biomolecular Sciences and Biotechnology, Laboratory of Molecular Physiology and Neurobiology, University of Milano and Instituto Nazionale Fisica della Materia-Milano U. Unit, via Celoria 26, 20133 Milano, Italy

Pacemaker channels are encoded by the HCN gene family and are responsible for a variety of cellular functions including control of spontaneous activity in cardiac myocytes and control of excitability in different types of neurons. Some of these functions require specific membrane localization. Although several voltage-gated channels are known to interact with intracellular proteins exerting auxiliary functions, no cytoplasmic proteins have been found so far to modulate HCN channels. Through the use of a yeast two-hybrid technique, here we showed that filamin A interacts with HCN1, an HCN isoform widely expressed in the brain, but not with HCN2 or HCN4. Filamin A is a cytoplasmic scaffold protein with actin-binding domains whose main function is to link transmembrane proteins to the actin cytoskeleton. Using several HCN1 C-terminal constructs, we identified a filamin A-interacting region of 22 amino acids located downstream from the cyclic nucleotide-binding domain; this region is not conserved in HCN2, HCN3, or HCN4. We also verified by immunoprecipitation from bovine brain that the filamin A-HCN1 interaction is functional in vivo. In filamin A-expressing cells (filamin⁺), HCN1 (but not HCN4) channels were expressed in hot spots, whereas they were evenly distributed on the membrane of cells lacking filamin A (filamin^–) indicating that interaction with filamin A affects membrane localization. Also, in filamin^– cells the gating kinetics of HCN1 were strongly accelerated relative to filamin⁺ cells. The interaction with filamin A may contribute to localizing HCN1 channels to specific neuronal areas and to modulating channel activity.

Received for publication, February 13, 2004 , and in revised form, July 20, 2004.

^* This work was supported by Ministero dell' Istruzione dell' Università e della Ricerca (MIUR) Cofin 2002 Grant 2002053813, Fondo Speciale per lo Sviluppo della Ricerca di Interesse Strategico (FSSRIS) Grant 02.00652.ST97, and Fondo per gli Investimenti della Ricerca di Base (FIRB) Grant 2002 RBNE01AAS7 (to D. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: University of Milano, Department of Biomolecular Sciences and Biotechnology, via Celoria 26, 20133 Milano, Italy. Tel.: 39-02-50314931; Fax: 39-02-50314932; E-mail: dario.difrancesco{at}unimi.it.

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