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J. Biol. Chem., Vol. 280, Issue 14, 13694-13700, April 8, 2005

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An Arginine Residue in the Pore Region Is a Key Determinant of Chloride Dependence in Cardiac Pacemaker Channels^*

Christian Wahl-Schott, Ludwig Baumann, Xiangang Zong, and Martin Biel

From the Department Pharmazie – Pharmakologie für Naturwissenschaften, Ludwig-Maximilians-Universität München, Butenandtstr. 7-13, 81377 München, Germany

The modulation of ion channel activity by extracellular ions plays a central role in the control of heart function. Here, we show that the sinoatrial pacemaker current I_f is strongly affected by the extracellular Cl^– concentration. We investigated the molecular basis of the Cl^– dependence in heterologously expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that represent the molecular correlate of I_f. Currents carried by the two cardiac HCN channel isoforms (HCN2 and HCN4) showed the same strong Cl^– dependence as the sinoatrial I_f and decreased to about 10% in the absence of external Cl^–. In contrast, the neuronal HCN1 current was reduced to only 50% under the same conditions. Depletion of Cl^– did not affect the voltage dependence of activation or the ion selectivity of the channels, indicating that the reduction of I_f was caused by a decrease of channel conductance. A series of chimeras between HCN1 and HCN2 was constructed to identify the structural determinants underlying the different Cl^– dependence of HCN1 and HCN2. Exchange of the ion-conducting pore region was sufficient to switch the Cl^– dependence from HCN1- to HCN2-type and vice versa. Replacement of a single alanine residue in the pore of HCN1 (Ala-352) by an arginine residue present in HCN2 at equivalent position (Arg-405) induced HCN2-type chloride sensitivity in HCN1. Our data indicate that Arg-405 is a key component of a domain that allosterically couples Cl^– binding with channel activation.

Received for publication, November 23, 2004 , and in revised form, January 7, 2005.

^* This work was supported by grants from Deutsche Forschungsgemeinschaft. 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: Dept. Pharmazie – Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München, Butenandtstrasse 7-13, 81377 München, Germany. Tel.: 49-89-2180-77327; Fax: 49-89-2180-77326; E-mail: mbiel{at}cup.unimuenchen.de.

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