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J. Biol. Chem., Vol. 281, Issue 3, 1796-1807, January 20, 2006

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Regulation of Sensory Neuron-specific Acid-sensing Ion Channel 3 by the Adaptor Protein Na⁺/H⁺ Exchanger Regulatory Factor-1^*

From the Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UNSA UMR 6097, Institut Paul Hamel, 660 Route des Lucioles, Sophia Antipolis, Valbonne 06560, France

Acid-sensing ion channels (ASICs) are cationic channels activated by extracellular protons. The ASIC3 subunit is largely expressed in the peripheral nervous system, where it contributes to pain perception and to some aspects of mechanosensation. We report here a PDZ-dependent and protein kinase C-modulated association between ASIC3 and the Na⁺/H⁺ exchanger regulatory factor-1 (NHERF-1) adaptor protein. We show that NHERF-1 and ASIC3 are co-expressed in dorsal root ganglion neurons. NHERF-1 enhances the ASIC3 peak current in heterologous cells, including F-11 dorsal root ganglion cells, by increasing the amount of channel at the plasma membrane. Perhaps more importantly, we show that the plateau current of ASIC3 can be dramatically increased (10-30-fold) by association with NHERF-1, leading to a significant sustained current at pH 6.6. In the presence of NHERF-1, the ASIC3 subcellular localization is modified, and the channel co-localizes with ezrin, a member of the ezrin-radixin-moesin family of actin-binding proteins, providing the first direct link between ASIC3 and the cortical cytoskeleton. Given the importance of the ASIC3 sustained current in nociceptor excitability, it is likely that NHERF-1 participates in channel functions associated with nociception and mechanosensation.

Received for publication, September 1, 2005

^* This work was supported by INSERM, the Institut Paul Hamel, the Association Française contre les Myopathie, the Association pour la Recherche sur le Cancer, and the Fondation pour la Recherche Médicale. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UNSA UMR 6097, 660 Route des Lucioles, Sophia Antipolis, Valbonne 06560, France. Tel.: 33-4-93-95-77-02 or -03; Fax: 33-4-93-95-77-04; E-mail: lazdunski{at}ipmc.cnrs.fr.

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