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G Interferes with Ca²⁺-Dependent Binding of Synaptotagmin to the Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor (SNARE) Complex

Department of Pharmacology, Vanderbilt University Medical School, Nashville, Tennessee (E.J.Y., B.D.S., H.E.H.); and Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois (T.G., S.A.).

Presynaptic inhibitory G protein-coupled receptors (GPCRs) can decrease neurotransmission by inducing interaction of G with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. We have shown that this action of G requires the carboxyl terminus of the 25-kDa synaptosome-associated protein (SNAP25) and is downstream of the well known inhibition of Ca²⁺ entry through voltage-gated calcium channels. We propose a mechanism in which G and synaptotagmin compete for binding to the SNARE complex. Here, we characterized the G interaction sites on syntaxin1A and SNAP25 and demonstrated an overlap of the G- and synaptotagmin I -binding regions on each member of the SNARE complex. Synaptotagmin competes in a Ca²⁺-sensitive manner with binding of G to SNAP25, syntaxin1A, and the assembled SNARE complex. We predict, based on these findings, that at high intracellular Ca²⁺ concentrations, Ca²⁺-synaptotagmin I can displace G binding and the G-dependent inhibition of exocytosis can be blocked. We tested this hypothesis in giant synapses of the lamprey spinal cord, where 5-HT works via G to inhibit neurotransmission (Blackmer et al., 2001). We showed that increased presynaptic Ca²⁺ suppresses the 5-HT- and G-dependent inhibition of exocytosis. We suggest that this effect may be due to Ca²⁺-dependent competition between G and synaptotagmin I for SNARE binding. This type of dynamic regulation may represent a novel mechanism for modifying transmitter release in a graded manner based on the history of action potentials that increase intracellular Ca²⁺ concentrations and of inhibitory signals through G_i-coupled GPCRs.

Address correspondence to: Heidi E. Hamm, Department of Pharmacology, Vanderbilt University Medical School, 23rd Ave. South at Pierce, Nashville, TN 37232. E-mail: heidi.hamm{at}vanderbilt.edu

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