Gβγ directly modulates vesicle fusion by competing with synaptotagmin for binding to neuronal SNARE proteins embedded in membranes.

The Journal of Biological Chemistry
Zack ZurawskiHeidi E Hamm

Abstract

Gi/o-coupled G protein-coupled receptors can inhibit neurotransmitter release at synapses via multiple mechanisms. In addition to Gβγ-mediated modulation of voltage-gated calcium channels (VGCC), inhibition can also be mediated through the direct interaction of Gβγ subunits with the soluble N-ethylmaleimide attachment protein receptor (SNARE) complex of the vesicle fusion apparatus. Binding studies with soluble SNARE complexes have shown that Gβγ binds to both ternary SNARE complexes, t-SNARE heterodimers, and monomeric SNAREs, competing with synaptotagmin 1(syt1) for binding sites on t-SNARE. However, in secretory cells, Gβγ, SNAREs, and synaptotagmin interact in the lipid environment of a vesicle at the plasma membrane. To approximate this environment, we show that fluorescently labeled Gβγ interacts specifically with lipid-embedded t-SNAREs consisting of full-length syntaxin 1 and SNAP-25B at the membrane, as measured by fluorescence polarization. Fluorescently labeled syt1 undergoes competition with Gβγ for SNARE-binding sites in lipid environments. Mutant Gβγ subunits that were previously shown to be more efficacious at inhibiting Ca2+-triggered exocytotic release than wild-type Gβγ were also shown to bind SNAREs at a high...Continue Reading

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Citations

Feb 3, 2019·The Journal of Biological Chemistry·Zack ZurawskiHeidi E Hamm
May 13, 2018·Neurochemical Research·Simon AlfordZack Zurawski
Nov 30, 2018·Frontiers in Molecular Neuroscience·Zhenxing RenDongfeng Chen
Apr 11, 2018·Proceedings of the National Academy of Sciences of the United States of America·Marjorie DamianJean-Louis Banères
Dec 12, 2019·Frontiers in Physiology·Aguan D Wei, Jan-Marino Ramirez
Oct 14, 2020·Proceedings of the National Academy of Sciences of the United States of America·Quanfeng ZhangZhuan Zhou
Feb 15, 2021·Cellular Signalling·Mithila TennakoonAjith Karunarathne

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