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Disabling the G??-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.

ABSTRACT: G protein-coupled receptors (GPCRs) that couple to G_i/o proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of G?? subunits from activated G proteins decreases the activity of voltage-gated Ca²⁺ channels (VGCCs), decreasing excitability. A less understood G??-mediated mechanism downstream of Ca²⁺ entry is the binding of G?? 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. SNAP25?3 homozygote mice exhibited normal presynaptic inhibition by GABA_B receptors, which inhibit VGCCs, but defective presynaptic inhibition by receptors that work directly on the SNARE complex, such as 5-hydroxytryptamine (serotonin) 5-HT_1b receptors and adrenergic ?_2a receptors. Simultaneously stimulating receptors that act through both mechanisms showed synergistic inhibitory effects. SNAP25?3 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_i/o-coupled GPCRs through the G??-SNARE interaction is a crucial component of numerous physiological and behavioral processes.

SUBMITTER: Zurawski Z

PROVIDER: S-EPMC7758873 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Disabling the Gβγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.

Zurawski Zack Z Thompson Gray Analisa D AD Brady Lillian J LJ Page Brian B Church Emily E Harris Nicholas A NA Dohn Michael R MR Yim Yun Young YY Hyde Karren K Mortlock Douglas P DP Jones Carrie K CK Winder Danny G DG Alford Simon S Hamm Heidi E HE

Science signaling 20190219 569

G protein-coupled receptors (GPCRs) that couple to Gi/o proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβγ subunits from activated G proteins decreases the activity of voltage-gated Ca2+ channels (VGCCs), decreasing excitability. A less understood Gβγ-mediated mechanism downstream of Ca2+ entry is the binding of Gβγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. He ...[more]

PMID: 30783011

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Dataset Information

Disabling the G??-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.

Publications

Disabling the Gβγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.

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