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J. Biol. Chem., Vol. 281, Issue 20, 14015-14025, May 19, 2006

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Integrin Receptor Activation Triggers Converging Regulation of Cav1.2 Calcium Channels by c-Src and Protein Kinase A Pathways^*

Peichun Gui, Xin Wu, Shizhang Ling^¶, Stephanie C. Stotz^||1, Robert J. Winkfein^||, Emily Wilson, George E. Davis, Andrew P. Braun^¶2, Gerald W. Zamponi^||3, and Michael J. Davis⁴

From the Department of Medical Pharmacology & Physiology, University of Missouri School of Medicine, Columbia, Missouri 65212, the Department of Systems Biology & Translational Medicine, Texas A&M University College of Medicine, College Station, Texas 77840, and the ^¶Smooth Muscle and ^||Cellular and Molecular Neurobiology Research Groups, University of Calgary School of Medicine, Calgary, Alberta T2N 4N1, Canada

L-type, voltage-gated Ca²⁺ channels (Ca_L) play critical roles in brain and muscle cell excitability. Here we show that currents through heterologously expressed neuronal and smooth muscle Ca_L channel isoforms are acutely potentiated following 51 integrin activation. Only the _1C pore-forming channel subunit is critical for this process. Truncation and site-directed mutagenesis strategies reveal that regulation of Cav1.2 by 51 integrin requires phosphorylation of _1C C-terminal residues Ser¹⁹⁰¹ and Tyr²¹²². These sites are known to be phosphorylated by protein kinase A (PKA) and c-Src, respectively, and are conserved between rat neuronal (Cav1.2c) and smooth muscle (Cav1.2b) isoforms. Kinase assays are consistent with phosphorylation of these two residues by PKA and c-Src. Following 51 integrin activation, native Ca_L channels in rat arteriolar smooth muscle exhibit potentiation that is completely blocked by combined PKA and Src inhibition. Our results demonstrate that integrin-ECM interactions are a common mechanism for the acute regulation of Ca_L channels in brain and muscle. These findings are consistent with the growing recognition of the importance of integrin-channel interactions in cellular responses to injury and the acute control of synaptic and blood vessel function.

Received for publication, January 17, 2006 , and in revised form, March 10, 2006.

^* This work was supported in part by operating grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Alberta and the Northwest Territories (to G. W. Z. and A. P. B.) and National Institutes of Health Grants HL-72989 (to M. J. D.) and RR-017353 to the University of Missouri. 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 nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) P22002 [GenBank] (_1C-c) and P15381 [GenBank] (_1C-b).

¹ Recipient of studentship awards from the Alberta Heritage Foundation for Medical Research and the Canadian Institutes of Health Research.

² Alberta Heritage Foundation for Medical Research Senior Scholar.

³ Senior Scholar of the Alberta Heritage Foundation for Medical Research and a Canada Research Chair in Molecular Neurobiology.

⁴ To whom correspondence should be addressed: 1 Hospital Drive, M451, Columbia, MO 65212. Tel.: 573-884-5181; Fax: 573-884-4276; E-mail: davismj{at}health.missouri.edu.

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