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J. Biol. Chem., Vol. 278, Issue 22, 19627-19633, May 30, 2003

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Munc18-Syntaxin Complexes and Exocytosis in Human Platelets^*

Aiilyan Houng , János Polgár  and Guy L. Reed   ¶

From the Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115 and Massachusetts General Hospital, Boston, Massachusetts 02114

The Sec1-Munc18 (SM) proteins are required for cellular exocytosis, but their mechanistic function remains poorly understood. We examined SM-syntaxin complexes in human platelets, which are terminally differentiated, anuclear cells that secrete the contents of their intracellular granules through syntaxin 2- and syntaxin 4-dependent mechanisms. Munc18a, Munc18b, and Munc18c were detected in human platelets by immunoblotting and/or PCR. The SM proteins and syntaxin 2 were found in the membrane and cytosolic fractions of cells, whereas syntaxin 4 was detected only in the membrane. Platelet membranes contain Munc18c-syntaxin 4 complexes, but minimal if any Munc18c-syntaxin 2 complexes were found. No significant amounts of Munc18a or Munc18b complexes were seen with either syntaxin. Munc18c-syntaxin 4 complexes were dissociated when cells were activated to secrete. Two potential inhibitors of Munc18c-syntaxin 4 complexes were generated to examine whether complex dissociation may lead to exocytosis. Peptides that mimic the projected intermolecular contact sites of Munc18c with syntaxin enhanced Ca²⁺-triggered dense granule exocytosis in permeabilized cells. Similarly, an anti-Munc18c monoclonal antibody that inhibited the Munc18c-syntaxin complex potently amplified Ca²⁺-induced platelet granule secretion. In summary, Munc18 proteins bind to specific syntaxin isoforms in platelets despite the presence of other potential binding partners. Acute inhibition of the SM-syntaxin complex promotes Ca²⁺-induced exocytosis, suggesting that complex formation per se has a regulatory effect on triggered secretion.

Received for publication, December 6, 2002 , and in revised form, March 19, 2003.

^* This work was supported in part by National Institutes of Health Grant HL-64057 and by an Established Investigator Award of the American Heart Association (to G. L. R.). 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.

^¶ To whom correspondence should be addressed: Cardiovascular Biology Laboratory, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. Tel.: 617-432-4992; Fax: 617-432-0033; E-mail: reed{at}cvlab.harvard.edu.

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