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Vol. 16, Issue 10, 4755-4764, October 2005

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Synaptotagmin Isoforms Couple Distinct Ranges of Ca²⁺, Ba²⁺, and Sr²⁺ Concentration to SNARE-mediated Membrane Fusion

Akhil Bhalla ^* , Ward C. Tucker ^*, and Edwin R. Chapman ^* 

^* Department of Physiology, University of Wisconsin, Madison, WI 53706; Molecular and Cellular Pharmacology Program, University of Wisconsin, Madison, WI 53706

Submitted April 3, 2005; Revised July 8, 2005; Accepted August 2, 2005
Monitoring Editor: Vivek Malhotra

Ca²⁺-triggered exocytosis of synaptic vesicles is controlled by the Ca²⁺-binding protein synaptotagmin (syt) I. Fifteen additional isoforms of syt have been identified. Here, we compared the abilities of three syt isoforms (I, VII, and IX) to regulate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion in vitro in response to divalent cations. We found that different isoforms of syt couple distinct ranges of Ca²⁺, Ba²⁺, and Sr²⁺ to membrane fusion; syt VII was 400-fold more sensitive to Ca²⁺ than was syt I. Omission of phosphatidylserine (PS) from both populations of liposomes completely abrogated the ability of all three isoforms of syt to stimulate fusion. Mutations that selectively inhibit syt·target-SNARE (t-SNARE) interactions reduced syt stimulation of fusion. Using Sr²⁺ and Ba²⁺, we found that binding of syt to PS and t-SNAREs can be dissociated from activation of fusion, uncovering posteffector-binding functions for syt. Our data demonstrate that different syt isoforms are specialized to sense different ranges of divalent cations and that PS is an essential effector of Ca²⁺·syt action.

Abbreviations used: IP, immunoprecipitation; PC, phosphatidylcholine; PS, phosphatidylserine; SNARE, soluble N-ethylmaleimide-sensitive factor attachment receptor; syt, synaptotagmin; VAMP, vesicle-associated membrane protein; cd VAMP; cytoplasmic domain of VAMP.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Address correspondence to: Edwin R. Chapman (chapman{at}physiology.wisc.edu).

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