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J. Biol. Chem., Vol. 278, Issue 52, 52273-52281, December 26, 2003

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Phosphorylation-regulated Inhibition of the G_z GTPase-activating Protein Activity of RGS Proteins by Synapsin I^*

Yaping Tu, Surendra K. Nayak, Jimmy Woodson, and Elliott M. Ross¶

From the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041

Synapsins are neuronal proteins that bind and cluster synaptic vesicles in the presynaptic space, presumably by anchoring to actin filaments, but specific regulatory functions of the synapsins are unknown. We found that a sub-population of brain synapsin Ia, a splice variant of one of three synapsin isoforms, inhibits the GTPase-activating protein (GAP) activity of several RGS proteins. Inhibition is highly selective for G_z, a member of the G_i family that is found in neurons, platelets, adrenal chromaffin cells, and a few other neurosecretory cells. G_z has been indirectly implicated in the regulation of secretion. Synapsin Ia constitutes a major fraction of the total GAP-inhibitory activity in brain, and its inhibitory activity is absent from the brains of synapsin I^-/-/II^-/- mice. Inhibition depends on the cationic D/E domain of synapsin. Phosphorylation of synapsin Ia at serine 9 by either cyclic AMP-dependent protein kinase or p21-activated protein kinase (PAK1) attenuates its potency as a GAP inhibitor more than 7-fold. Synapsin can thus act as a phosphorylation-modulated mediator of feedback regulation of G_z signaling by the synaptic machinery.

Received for publication, August 29, 2003 , and in revised form, October 9, 2003.

^* This work was supported by United States Public Health Services Grant GM30355 and by R. A. Welch Foundation Grant I-0982. 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.

Present address: Dept. of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178.

Present address: RNA Profiling, Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.

^¶ To whom correspondence should be addressed: Dept. of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9041. Tel.: 214-648-8717; Fax: 214-648-2994; E-mail: ross{at}utsw.swmed.edu.

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