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J. Biol. Chem., Vol. 281, Issue 34, 24104-24110, August 25, 2006

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The ₁--Subunit Interaction That Modulates Calcium Channel Activity Is Reversible and Requires a Competent -Interaction Domain^*

Patricia Hidalgo, Giovanni Gonzalez-Gutierrez^¶, Jennie Garcia-Olivares, and Alan Neely^¶1

From the Abteilung Neurophysiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany, the Centro de Estudios Científicos, Valdivia 509000, Chile, and the ^¶Centro de Neurociencia de Valparaíso, Universidad de Valparaíso 2349400 Valparaíso, Chile

High voltage-gated calcium channels consist of a pore-forming subunit (₁) and three nonhomologous subunits (₂/, , and ). Although it is well established that the -subunit promotes traffic of channels to the plasma membrane and modifies their activity, the reversible nature of the interaction with the ₁-subunit remains controversial. Here, we address this issue by examining the effect of purified _2a protein on Ca_V1.2 and Ca_V2.3 channels expressed in Xenopus oocytes. The _2a-subunit binds to the ₁-interaction domain (AID) in vitro, and when injected into oocytes, it shifts the voltage dependence of activation and increases charge movement to ionic current coupling of Ca_V1.2 channels. This increase depended on the integrity of AID but was not abolished by bafilomycin, demonstrating that the ₁- interaction through the AID site can take place at the plasma membrane. Furthermore, injection of _2a protein inhibited inactivation of Ca_V2.3 channels and converted fast inactivating Ca_V2.3/_1b channels to slow inactivating channels. Inhibition of inactivation required larger concentration of _2a in oocytes expressing Ca_V2.3/_1b channels than expressing Ca_V2.3 alone but reached the same maximal level as expected for a competitive interaction through a single binding site. Together, our data show that the ₁- interaction is reversible in intact cells and defines calcium channels -subunits as regulatory proteins rather than stoichiometric subunits.

Received for publication, June 21, 2006

^* This work was supported by Fondo Nacional de Ciencia y Tecnología Grants 1020899 and Anillo de Ciencia y Tecnología-46 (to A. N.) and by Deutsche Forschungsgemeinschaft Grant FOR 450, TP 1 (to P. H.). 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.

¹ To whom correspondence should be addressed: Centro de Neurociencia de Valparaíso, Facultad de Ciencias, Universidad de Valparaíso, Gran Bretaña 1111, Valparaíso, 2349400 Chile. Tel.: 56-32-508054; Fax: 56-32-283320; E-mail: alan{at}cnv.cl.

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