Munc18-dependent regulation of synaptic vesicle exocytosis by syntaxin-1A in hippocampal neurons.

TitleMunc18-dependent regulation of synaptic vesicle exocytosis by syntaxin-1A in hippocampal neurons.
Publication TypeJournal Article
Year of Publication2005
AuthorsMitchell SJ, Ryan TA
Date Published2005 Mar
KeywordsAnimals, Antigens, Surface, Cells, Cultured, Exocytosis, Hippocampus, Munc18 Proteins, Nerve Tissue Proteins, Neurons, Rats, Synaptic Vesicles, Syntaxin 1, Vesicular Transport Proteins

The fusion of secretory vesicles with the plasma membrane requires the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes between the vesicle-SNARE vesicle-associated membrane protein present on the vesicular membrane and the target-SNAREs SNAP-25 and syntaxin-1A. Syntaxin-1A fluctuates between an open and closed form allowing it to selectively bind to different biological effectors in different conformations. In the open form, it can participate in SNARE complex formation, however, in the closed form it negatively regulates N- and P/Q-type voltage-dependent calcium channels, and is capable of inhibiting calcium influx. Thus paradoxically, syntaxin appears to have both positive and negative roles in controlling calcium-driven synaptic vesicle fusion at synaptic terminals. We show here that overexpression of syntaxin-1A inhibited exocytosis, in a manner that could be rescued by either elevating or reducing external calcium, or increasing action potential firing frequency. Elevating the level of Munc18 by coexpression with syntaxin-1A also abolished this inhibition, suggesting that Munc18 serves to limit the negative regulatory role of syntaxin by binding to, and thereby buffering, its closed form. Our results also indicate that syntaxin can control the frequency-response characteristics of the presynaptic fusion machinery.

Alternate JournalNeuropharmacology
PubMed ID15721169
Grant ListGM61925 / GM / NIGMS NIH HHS / United States
NS24692 / NS / NINDS NIH HHS / United States
R01 NS036942 / NS / NINDS NIH HHS / United States