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J. Biol. Chem., Vol. 283, Issue 31, 21799-21807, August 1, 2008

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Analysis of the Synaptotagmin Family during Reconstituted Membrane Fusion

UNCOVERING A CLASS OF INHIBITORY ISOFORMS^*

Akhil Bhalla¹, Michael C. Chicka^¶12, and Edwin R. Chapman^¶3

From the Howard Hughes Medical Institute and the Departments of Physiology and ^¶Cellular and Molecular Biology, University of Wisconsin, Madison, Wisconsin 53706

Ca²⁺-triggered exocytosis in neurons and neuroendocrine cells is regulated by the Ca²⁺-binding protein synaptotagmin (syt) I. Sixteen additional isoforms of syt have been identified, but little is known concerning their biochemical or functional properties. Here, we assessed the abilities of fourteen syt isoforms to directly regulate SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor)-catalyzed membrane fusion. One group of isoforms stimulated neuronal SNARE-mediated fusion in response to Ca²⁺, while another set inhibited SNARE catalyzed fusion in both the absence and presence of Ca²⁺. Biochemical analysis revealed a strong correlation between the ability of syt isoforms to bind 1,2-dioleoyl phosphatidylserine (PS) and t-SNAREs in a Ca²⁺-promoted manner with their abilities to enhance fusion, further establishing PS and SNAREs as critical effectors for syt action. The ability of syt I to efficiently stimulate fusion was specific for certain SNARE pairs, suggesting that syts might contribute to the specificity of intracellular membrane fusion reactions. Finally, a subset of inhibitory syts down-regulated the ability of syt I to activate fusion, demonstrating that syt isoforms can modulate the function of each other.

Received for publication, November 27, 2007 , and in revised form, April 29, 2008.

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^* This work was supported, in whole or in part, by the National Institutes of Health. This work was also supported by the American Heart Association (to E. R. C.). 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.

¹ These authors contributed equally to this work.

² Funded by an American Heart Association pre-doctoral fellowship.

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³ An Investigator of the Howard Hughes Medical Institute. To whom correspondence should be addressed: Howard Hughes Medical Institute and Dept. of Physiology, University of Wisconsin, 1300 University Ave., SMI 129, Madison, WI 53706. Tel.: 608-263-1762; Fax: 608-265-5512; E-mail: chapman{at}physiology.wisc.edu.

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