Nature Neuroscience8, 421 - 425 (2005)
Published online: 20 March 2005; | doi:10.1038/nn1423
G protein directly regulates SNARE protein fusion machinery for secretory granule exocytosis
Trillium Blackmer1, 4, Eric C Larsen2, 4, Cheryl Bartleson3, Judith A Kowalchyk2, Eun-Ja Yoon3, Anita M Preininger3, Simon Alford1, Heidi E Hamm3
& Thomas F J Martin2
1
Department of Biological Sciences, University of Illinois at Chicago, 840 West Taylor Street, Chicago, Illinois 60607, USA.
2
Department of Biochemistry, University of Wisconsin, 433 Babcock Drive, Madison, Wisconsin 53706, USA.
3
Department of Pharmacology, Vanderbilt University School of Medicine, 23rd Avenue South at Pierce Avenue, Nashville, Tennessee 37232, USA.
The activation of G protein−coupled receptors (GPCRs) can result in an inhibition of Ca2+-dependent hormone and neurotransmitter secretion. This has been attributed in part to G protein inhibition of Ca2+ influx. However, a frequently dominant inhibitory effect, of unknown mechanism, also occurs distal to Ca2+ entry. Here we characterize direct inhibitory actions of G protein (G) on Ca2+-triggered vesicle exocytosis in permeable PC12 cells. G inhibition was rapid (<1 s) and was attenuated by cleavage of synaptosome-associated protein of 25 kD (SNAP25). G bound soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, and binding was reduced to SNARE complexes containing cleaved SNAP25 or by Ca2+-dependent synaptotagmin binding. Here we show inhibitory coupling between GPCRs and vesicle exocytosis mediated directly by G interactions with the Ca2+-dependent fusion machinery.
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directly regulates SNARE protein fusion machinery for secretory granule exocytosis
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