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GPCR regulation of secretion.

ABSTRACT: Modulation of neurotransmitter exocytosis by activated Gi/o coupled G-protein coupled receptors (GPCRs) is a universal regulatory mechanism used both to avoid overstimulation and to influence circuitry. One of the known modulation mechanisms is the interaction between G?? and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNAREs). There are 5 G? and 12 G? subunits, but specific G??s activated by a given GPCR and the specificity to effectors, such as SNARE, in vivo are not known. Although less studied, G?? binding to the exocytic fusion machinery (i.e. SNARE) provides a more direct regulatory mechanism for neurotransmitter release. Here, we review some recent insights in the architecture of the synaptic terminal, modulation of synaptic transmission, and implications of G protein modulation of synaptic transmission in diseases. Numerous presynaptic proteins are involved in the architecture of synaptic terminals, particularly the active zone, and their importance in the regulation of exocytosis is still not completely understood. Further understanding of the G??-SNARE interaction and the architecture and mechanisms of exocytosis may lead to the discovery of novel therapeutic targets to help patients with various disorders such as hypertension, attention-deficit/hyperactivity disorder, post-traumatic stress disorder, and acute/chronic pain.

SUBMITTER: Yim YY

PROVIDER: S-EPMC6263855 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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GPCR regulation of secretion.

Yim Yun Young YY Zurawski Zack Z Hamm Heidi H

Pharmacology & therapeutics 20180726

Modulation of neurotransmitter exocytosis by activated G<sub>i/o</sub> coupled G-protein coupled receptors (GPCRs) is a universal regulatory mechanism used both to avoid overstimulation and to influence circuitry. One of the known modulation mechanisms is the interaction between Gβγ and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNAREs). There are 5 Gβ and 12 Gγ subunits, but specific Gβγs activated by a given GPCR and the specificity to effectors, such as SNARE, ...[more]

PMID: 30056056

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Project description:Background and purposeMany GPCRs, including the CB(1) cannabinoid receptor, are down-regulated following prolonged agonist exposure by interacting with the GPCR-associated sorting protein-1 (GASP-1). The CB(1) receptor antagonist rimonabant has also recently been described to be an agonist at GPR55, a cannabinoid-related receptor. Here we investigated the post-endocytic properties of GPR55 after agonist exposure and tested whether GASP-1 is involved in this process.Experimental approachWe evaluated the direct protein-protein interaction of GPR55 with GASP-1 using (i) GST-binding assays and (ii) co-immunoprecipitation assays in GPR55-HEK293 cells with endogenous GASP-1 expression. We further tested the internalization, recycling and degradation of GPR55 using confocal fluorescence microscopy and biotinylation assays in the presence and absence of GASP-1 (lentiviral small hairpin RNA knockdown of GASP-1) under prolonged agonist [rimonabant (RIM), lysophosphatidylinositol (LPI)] stimulation.Key resultsWe showed that the prolonged activation of GPR55 with rimonabant or LPI down-regulates GPR55 via GASP-1. GASP-1 binds to GPR55 in vitro, and this interaction was required for targeting GPR55 for degradation. Disrupting the GPR55-GASP-1 interaction prevented post-endocytic receptor degradation, and thereby allowed receptor recycling.Conclusion and implicationsThese data implicate GASP-1 as an important regulator of ligand-mediated down-regulation of GPR55. By identifying GASP-1 as a key regulator of the trafficking and, by extension, functional expression of GPR55, we may be one step closer to gaining a better understanding of this receptor in response to cannabinoid drugs.Linked articlesThis article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

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GPCR regulation of secretion.

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GPCR regulation of secretion.

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