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Papers In Press, published online ahead of print March 20, 2003
Cardiovascular Biology Laboratory, Harvard School of Public Health II-127, Boston, MA 02115
Corresponding Author: reed{at}cvlab.harvard.edu
The Sec1-Munc18 (SM)1 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 while 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.
J. Biol. Chem, 10.1074/jbc.M212465200
Submitted on December 6, 2002
Revised on March 20, 2003
Accepted on March 20, 2003
Munc18-syntaxin complexes and exocytosis in human platelets
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