G protein βγ directly regulates SNARE protein fusion machinery for secretory granule exocytosis

Department of Biological Sciences, University of Illinois at Chicago, 840 West Taylor Street, Chicago, Illinois 60607, USA.
Nature Neuroscience (Impact Factor: 16.1). 04/2005; 8(4):421-5. DOI: 10.1038/nn1423
Source: PubMed


The activation of G protein-coupled receptors (GPCRs) can result in an inhibition of Ca(2+)-dependent hormone and neurotransmitter secretion. This has been attributed in part to G protein inhibition of Ca(2+) influx. However, a frequently dominant inhibitory effect, of unknown mechanism, also occurs distal to Ca(2+) entry. Here we characterize direct inhibitory actions of G protein betagamma (Gbetagamma) on Ca(2+)-triggered vesicle exocytosis in permeable PC12 cells. Gbetagamma inhibition was rapid (<1 s) and was attenuated by cleavage of synaptosome-associated protein of 25 kD (SNAP25). Gbetagamma bound soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, and binding was reduced to SNARE complexes containing cleaved SNAP25 or by Ca(2+)-dependent synaptotagmin binding. Here we show inhibitory coupling between GPCRs and vesicle exocytosis mediated directly by Gbetagamma interactions with the Ca(2+)-dependent fusion machinery.

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    • "Released GABA can feed back onto GABAB auto-receptors located on GABAergic terminals, and/or spillover to activate hetero-synaptic GABAB-Rs on neighboring glutamatergic terminals. Activation of the pre-synaptic GABAB-Rs inhibits neurotransmitter release through multiple targets including inactivation of voltage-dependent calcium channels (Mintz and Bean, 1993), gating of potassium conductance to shunt pre-synaptic action potentials (Thompson and Gahwiler, 1992a), reduction of vesicle priming (Sakaba and Neher, 2003), or interaction with the exocytosis machinery (Blackmer et al., 2005). Released GABA also signals onto post-synaptic GABAB-Rs located on dendritic shaft and spines (Kulik et al., 2003). "
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    Frontiers in Cellular Neuroscience 11/2013; 7:206. DOI:10.3389/fncel.2013.00206 · 4.29 Impact Factor
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    • "Since Gbg is known to directly bind to and inhibit voltagegated calcium channels, this study also tested the possibility that such binding could play a role in presynaptic LTD. Calcium imaging revealed that induction of LTD was associated with only a transient decrease in stimulus-evoked Ca 2þ influx that, while possibly contributing to short-term plasticity of release, could not underlie LTD, suggesting rather mechanisms downstream of calcium entry (Blackmer et al., 2005, 2001; Chen et al., 2005; Delaney et al., 2007; Gerachshenko et al., 2005; Takahashi et al., 2001). "
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    Neuropharmacology 05/2012; 66. DOI:10.1016/j.neuropharm.2012.05.004 · 5.11 Impact Factor
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    • "GABAB-Rs and mGluRs modulate neuronal excitability and synaptic plasticity through actions on pre- and/or post- synaptic targets. Activation of mGluRs (mainly, group II & II) & GABAB-Rs expressed on glutamatergic- and GABA-ergic- axon terminals regulate neurotransmitter release by inhibiting presynaptic VGCCs and/or by interfering directly with the transmitter release machinery [63], [64]. Stimulation of mGluRs (mainly, group I), localized on postsynaptic neurons, depolarize them through actions on various Ca2+, K+ and other non-specific cationic conductances [64], [65]. "
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