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J. Biol. Chem., Vol. 282, Issue 29, 21392-21403, July 20, 2007

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Ca²⁺-dependent Activator Protein for Secretion 1 Is Critical for Constitutive and Regulated Exocytosis but Not for Loading of Transmitters into Dense Core Vesicles^*

Yoshihito Fujita¹, Ainan Xu¹, Li Xie^¶1, Lakshmanan Arunachalam¹, Ting-Chieh Chou, Tiandan Jiang, Soon-Kwang Chiew, John Kourtesis, Li Wang, Herbert Y. Gaisano^¶, and Shuzo Sugita²

From the Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network and the Departments of Physiology and ^¶Medicine, University of Toronto, Toronto, Ontario M5T 2S8, Canada

Although CAPS1 was originally identified as a soluble factor that reconstitutes Ca²⁺-dependent secretion from permeabilized neuroendocrine cells, its exact function in intact mammalian cells remains controversial. Here we investigate the role for CAPS1 by generating stable cell lines in which CAPS1 is strongly down-regulated. In these cells, Ca²⁺-dependent secretion was strongly reduced not only of catecholamine but also of a transfected neuropeptide. These secretion defects were rescued by infusion of CAPS1-containing brain cytosol or by transfection-mediated expression of CAPS1. Whole cell patch clamp recording revealed significant reductions in slow burst and sustained release components of exocytosis in the knockdown cells. Unexpectedly, they also accumulated higher amounts of endogenous and exogenous transmitters, which were attributable to reductions in constitutive secretion. Electron microscopy did not reveal abnormalities in the number or docking of dense core vesicles. Our results indicate that CAPS1 plays critical roles not only in Ca²⁺-dependent, regulated exocytosis but also in constitutive exocytosis downstream of vesicle docking. However, they do not support the role for CAPS1 in loading transmitters into dense core vesicles.

Received for publication, May 4, 2007 , and in revised form, May 29, 2007.

^* This work was supported by the Canada Research Chair program, the Natural Sciences and Engineering Research Council of Canada (Grant 456042), the Canadian Institute of Health Research (Grants MOP-57825 and MOP-64465), and the Canadian Diabetes Association (Grant GA-2-06-2115-HG). 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 and S2.

¹ These authors contribute equally to this work.

² To whom correspondence should be addressed: Toronto Western Research Institute, MC11-432, University Health Network, 399 Bathurst St., MC11-432, Toronto, Ontario M5T 2S8, Canada. Tel.: 416-603-5077; Fax: 416-603-5745; E-mail: ssugita{at}uhnres.utoronto.ca.

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