Publication Date:
2019
Description:
〈p〉G protein–coupled receptors (GPCRs) that couple to G〈sub〉i/o〈/sub〉 proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβ subunits from activated G proteins decreases the activity of voltage-gated Ca〈sup〉2+〈/sup〉 channels (VGCCs), decreasing excitability. A less understood Gβ-mediated mechanism downstream of Ca〈sup〉2+〈/sup〉 entry is the binding of Gβ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially deficient in this interaction. SNAP253 homozygote mice exhibited normal presynaptic inhibition by GABA〈sub〉B〈/sub〉 receptors, which inhibit VGCCs, but defective presynaptic inhibition by receptors that work directly on the SNARE complex, such as 5-hydroxytryptamine (serotonin) 5-HT〈sub〉1b〈/sub〉 receptors and adrenergic α〈sub〉2a〈/sub〉 receptors. Simultaneously stimulating receptors that act through both mechanisms showed synergistic inhibitory effects. SNAP253 homozygote mice had various behavioral phenotypes, including increased stress-induced hyperthermia, defective spatial learning, impaired gait, and supraspinal nociception. These data suggest that the inhibition of exocytosis by G〈sub〉i/o〈/sub〉-coupled GPCRs through the Gβ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.〈/p〉
Print ISSN:
1945-0877
Electronic ISSN:
1937-9145
Topics:
Biology
,
Medicine
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