Disabling Gβγ SNARE interaction in transgenic mice disrupts GPCR-mediated presynaptic inhibition leading to physiological and behavioral phenotypes.

Zurawski, Z.; Thompson Gray, A. D.; Brady, L. J.; Page, B.; Church, E.; Harris, N. A.; Dohn, M. R.; Yim, Y. Y.; Hyde, K.; Mortlock, D. P.; Winder, D. G.; Alford, S.; Jones, C. K.; Hamm, H. E.

doi:10.1101/280347

bioRxiv · 10.1101/280347

Disabling Gβγ SNARE interaction in transgenic mice disrupts GPCR-mediated presynaptic inhibition leading to physiological and behavioral phenotypes.

Zurawski, Z.·Thompson Gray, A. D.·Brady, L. J.·Page, B.·Church, E.·Harris, N. A.·Dohn, M. R.·Yim, Y. Y.·Hyde, K.·Mortlock, D. P.·Winder, D. G.·Alford, S.·Jones, C. K.·Hamm, H. E.

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Abstract

Gi/o-coupled G-protein coupled receptors modulate neurotransmission presynaptically through inhibition of exocytosis. Release of G{beta}{gamma} subunits decreases the activity of voltage-gated calcium channels (VGCC), decreasing excitability. A less understood G{beta}{gamma}-mediated mechanism downstream of calcium entry is the binding of G{beta}{gamma} to SNARE complexes. Here, we create a mouse partially deficient in this interaction. SNAP25{Delta}3 homozygote animals are developmentally normalbut impaired gait and supraspinal nociception. They also have elevated stress-induced hyperthermia and impaired inhibitory postsynaptic responses to 2A-AR, but normal inhibitory postsynaptic responses to Gi/o-coupled GABAB receptor activation. SNAP25{Delta}3 homozygotes have deficits in inhibition of hippocampal postsynaptic responses to 5 HT1b agonists that affect hippocampal learning. These data suggest that Gi/o-coupled GPCR inhibition of exocytosis through the G{beta}{gamma}-SNARE interaction is a crucial component of numerous physiological and behavioral processes.

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Zurawski, Z., Thompson Gray, A. D., Brady, L. J., Page, B., Church, E., Harris, N. A., Dohn, M. R., Yim, Y. Y., Hyde, K., Mortlock, D. P., Winder, D. G., Alford, S., Jones, C. K., Hamm, H. E.. 2018-03-11. Disabling Gβγ SNARE interaction in transgenic mice disrupts GPCR-mediated presynaptic inhibition leading to physiological and behavioral phenotypes.. https://doi.org/10.1101/280347

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