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J. Biol. Chem., Vol. 282, Issue 4, 2156-2162, January 26, 2007

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The Src Homology 3 Domain of the -Subunit of Voltage-gated Calcium Channels Promotes Endocytosis via Dynamin Interaction^*

Giovanni Gonzalez-Gutierrez¹, Erick Miranda-Laferte¹, Alan Neely, and Patricia Hidalgo²

From the Centro de Neurociencia de Valparaíso, Universidad de Valparaíso 2349400 Chile and the Abteilung Neurophysiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany

High voltage-gated calcium channels enable calcium entry into cells in response to membrane depolarization. Association of the auxiliary -subunit to the -interaction-domain in the pore-forming ₁-subunit is required to form functional channels. The -subunit belongs to the membrane-associated guanylate kinase class of scaffolding proteins containing a Src homology 3 and a guanylate kinase domain. Although the latter is responsible for the high affinity binding to the -interaction domain, the functional significance of the Src homology 3 domain remains elusive. Here, we show that injection of isolated -subunit Src homology 3 domain into Xenopus laevis oocytes expressing the ₁-subunit reduces the number of channels in the plasma membrane. This effect is reverted by coexpressing ₁ with a dominant-negative mutant of dynamin, a GTPase involved in receptor-mediated endocytosis. Full-length -subunit also down-regulates voltage-gated calcium channels but only when lacking the -interaction domain. Moreover, isolated Src homology 3 domain and the full-length -subunit were found to interact in vitro with dynamin and to internalize the distantly related Shaker potassium channel. These results demonstrate that the -subunit regulates the turnover of voltagegated calcium channels and other proteins in the cell membrane. This effect is mediated by dynamin and depends on the association state of the -subunit to the ₁-pore-forming subunit. Our findings define a novel function for the -subunit through its Src homology 3 domain and establish a link between voltage-gated calcium channel activity and the cell endocytic machinery.

Received for publication, September 25, 2006 , and in revised form, November 14, 2006.

^* This work was supported by grants from the Deutsche Forschung Gemeinschaft (Grant FOR 450, TP1) (to P. H.) and the Fondo para el Desarrollo de Ciencia y Tecnologia (Grant FONDECYT-1020899) and Anillo de Ciencia y Tecnologia (Grant ACT-46) (to A. N.). The authors declare no competing financial interests. 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 tables and figures and equations.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Medizinische Hochschule Hannover, Abteilung Neurophysiologie, Carl-Neuberg-Str. 1, 30625 Hannover. Tel.: 49-511-532-2883; Fax: 49-511-532-2776; E-mail: hidalgo.patricia{at}mh-hannover.de.

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