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J. Biol. Chem., Vol. 281, Issue 41, 31131-31141, October 13, 2006

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Arrestin Is Required for Agonist-induced Trafficking of Voltage-dependent Calcium Channels^*

From the Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, New York 10029

Many metabotropic receptors in the nervous system act through signaling pathways that result in the inhibition of voltage-dependent calcium channels. Our previous findings showed that activation of seven-transmembrane receptors results in the internalization of calcium channels. This internalization takes place within a few seconds, raising the question of whether the endocytic machinery is in close proximity to the calcium channel to cause such rapid internalization. Here we show that voltage-dependent calcium channels are pre-associated with arrestin, a protein known to play a role in receptor trafficking. Upon GABA_B receptor activation, receptors are recruited to the arrestin-channel complex and internalized. -Arrestin 1 selectively binds to the SNARE-binding region of the calcium channel. Peptides containing the arrestin-binding site of the channel disrupt agonist-induced channel internalization. Taken together these data suggest a novel neuronal role for arrestin.

Received for publication, May 24, 2006 , and in revised form, August 15, 2006.

^* This work was supported by National Institutes of Health Grant NS 37443 and a Hirschl Trust Fund Career Development Award (to M. A. D.-P.). Confocal laser microscopy was performed at the MSSM-Microscopy Shared Facility, supported with funding from National Institutes of Health NCI Shared resources Grant 1R24 CA095823 and National Science Foundation Major Research Instrumentation Grant DBI-9724504. 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 Figs. S1-S5.

¹ To whom correspondence should be addressed: One Gustave L. Levy Place, Box 1603, New York, NY 10029. Tel.: 212-241-5569; Fax: 212-996-7214; E-mail: maria.diverse{at}mssm.edu.

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