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Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA

The formation and dissolution of SNARE protein complexes is essential for Ca²⁺-triggered fusion of neurotransmitter-filled vesicles at the presynaptic membrane. Among the pre-synaptic SNARE proteins, the activation of the Q-SNARE syntaxin1A is a critical event for SNARE complex formation. Activation requires syntaxin1A to transit from a munc18-bound non-interacting state to one competent for SNARE binding. The molecular mechanisms that regulate this transition remain unclear. The propensity of syntaxin1A to promote voltage-dependent steady-state inactivation of N-type Ca²⁺ channels and accelerate their entry into inactivation was used in a heterologous cell expression system to elucidate regulation of syntaxin1A protein–protein interactions. We report that coexpression of munc18 eliminated the promoting effect of syntaxin1A on inactivation. This effect of munc18 was completely disrupted by coexpression of munc13-1, but not munc13-2 or munc13-3. Also, since expression of munc13-1 with syntaxin1A resulted in an inactivation phenotype identical to that of munc18 with syntaxin1A, the action of munc13-1 on the munc18–syntaxin1A complex was functionally unique and did not result from competitive binding interactions. Furthermore, munc13 expressed with syntaxin1A and munc18 promoted redistribution of a cytosolic SNAP25 mutant to the membrane, a result indicative of syntaxin1A–SNAP25 SNARE pairing. These data demonstrate an important role of munc13 to control the protein–protein interactions of syntaxin1A in vivo, and support munc13 as critical to dissociating syntaxin1A–munc18 complexes and making syntaxin1A available for SNARE interactions.

(Received 26 April 2004; accepted after revision 11 June 2004; first published online 24 June 2004)
Corresponding author S. E. Gladycheva: 7804 Medical Sciences II Building, Department of Molecular and Integrative Physiology, The Medical School, University of Michigan, Ann Arbor, MI 48109-0622, USA. Email: segladys{at}umich.edu

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