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J. Biol. Chem., Vol. 279, Issue 43, 45004-45012, October 22, 2004

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Calmodulin Mediates Ca²⁺ Sensitivity of Sodium Channels^*

James Kim, Smita Ghosh, Huajun Liu, Michihiro Tateyama, Robert S. Kass, and Geoffrey S. Pitt¶||

From the Departments of Pharmacology and ^¶Medicine, Division of Cardiology, Columbia University, New York, New York 10032

Ca²⁺ has been proposed to regulate Na⁺ channels through the action of calmodulin (CaM) bound to an IQ motif or through direct binding to a paired EF hand motif in the Na_v1 C terminus. Mutations within these sites cause cardiac arrhythmias or autism, but details about how Ca²⁺ confers sensitivity are poorly understood. Studies on the homologous Ca_v1.2 channel revealed non-canonical CaM interactions, providing a framework for exploring Na⁺ channels. In contrast to previous reports, we found that Ca²⁺ does not bind directly to Na⁺ channel C termini. Rather, Ca²⁺ sensitivity appears to be mediated by CaM bound to the C termini in a manner that differs significantly from CaM regulation of Ca_v1.2. In Na_v1.2 or Na_v1.5, CaM bound to a localized region containing the IQ motif and did not support the large Ca²⁺-dependent conformational change seen in the Ca_v1.2·CaM complex. Furthermore, CaM binding to Na_v1 C termini lowered Ca²⁺ binding affinity and cooperativity among the CaM-binding sites compared with CaM alone. Nonetheless, we found suggestive evidence for Ca²⁺/CaM-dependent effects upon Na_v1 channels. The R1902C autism mutation conferred a Ca²⁺-dependent conformational change in Na_v1.2 C terminus·CaM complex that was absent in the wild-type complex. In Na_v1.5, CaM modulates the Cterminal interaction with the III–IV linker, which has been suggested as necessary to stabilize the inactivation gate, to minimize sustained channel activity during depolarization, and to prevent cardiac arrhythmias that lead to sudden death. Together, these data offer new biochemical evidence for Ca²⁺/CaM modulation of Na⁺ channel function.

Received for publication, June 29, 2004 , and in revised form, August 9, 2004.

^* This work was supported by grants from the National Institutes of Health (HL-71165 to G. S. P. and HL-56810 and HL-67849 to R. S. K.) and the Irma T. Hirschl Trust (to G. S. P.). 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Dept. of Pharmacology, Columbia University College of Physicians and Surgeons, 630 W. 168th St., PH 7W 318, New York, NY 10032. Tel.: 212-305-1009; Fax: 212-305-8780; E-mail: gp2004{at}columbia.edu.

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