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J. Biol. Chem., Vol. 279, Issue 6, 4102-4109, February 6, 2004

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Identification of Sites Responsible for Potentiation of Type 2.3 Calcium Currents by Acetyl--methylcholine^*

Ganesan L. Kamatchi, Ruthie Franke, Carl Lynch, III, and Julianne J. Sando

From the Department of Anesthesiology, University of Virginia Health Sciences Systems, Charlottesville, Virginia 22908-0710

To address mechanisms for the differential sensitivity of voltage-gated Ca²⁺ channels (Ca_v) to agonists, channel activity was compared in Xenopus oocytes coexpressing muscarinic M₁ receptors and different Ca_v 1 subunits, all with 1B,2/ subunits. Acetyl--methylcholine (MCh) decreased Ca_v 1.2c currents, did not affect 2.1 or 2.2 currents, but potentiated Ca_v 2.3 currents. Phorbol 12-myristate 13-acetate (PMA) did not affect Ca_v 1.2c or 2.1 currents but potentiated 2.2 and 2.3 currents. Comparison of the amino acid sequences of the ₁ subunits revealed a set of potential protein kinase C phosphorylation sites in common between the 2.2 and 2.3 channels that respond to PMA and a set of potential sites unique to the ₁ 2.3 subunits that respond to MCh. Quadruple Ser Ala mutation of the predicted MCh sites in the ₁ 2.3 subunit (Ser-888, Ser-892, and Ser-894 in the II–III linker and Ser-1987 in the C terminus) caused loss of the MCh response but not the PMA response. Triple Ser Ala mutation of just the II–III linker sites gave similar results. Ser-888 or Ser-892 was sufficient for the MCh responsiveness, whereas Ser-894 required the presence of Ser-1987. Ser Asp substitution of Ser-888, Ser-892, Ser-1987, and Ser-892/Ser-1987 increased the basal current and decreased the MCh response but did not alter the PMA response. These results reveal that sites unique to the II–III linker of ₁ 2.3 subunits mediate the responsiveness of Ca_v 2.3 channels to MCh. Because Ca_v 2.3 channels contribute to action potential-induced Ca²⁺ influx, these sites may account for M₁ receptor-mediated regulation of neurotransmission at some synapses.

Received for publication, August 5, 2003 , and in revised form, November 14, 2003.

^* This work was supported by National Institutes of Health Grants GM65214 (to G. L. K.) and GM31184 (to J. J. S.) and by the Department of Anesthesiology, University of Virginia Health Sciences Systems. 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. of Anesthesiology, P. O. Box 800710, University of Virginia Health Sciences System, 1766 Lane Rd., Charlottesville, VA 22908-0710. Tel.: 434-924-2924; Fax: 434-982-0019; E-mail: gk3p{at}virginia.edu.

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