The specificity of Gβγ subunits regulating exocytosis through the adrenergic α2a receptor

Abstract

Listen

Translate article

Modulation of neurotransmitter exocytosis by Gi/o‐coupled GPCRs, such as the α2a adrenergic receptor (α2a‐AR), is a universal regulatory mechanism used to avoid overstimulation and to influence circuitry. In addition to interaction with voltage‐gated calcium channels, Gβγ release through α2a‐AR directly interact with SNARE protein to inhibit exocytosis. It has been shown that these regulatory mechanisms by both presynaptic α2a‐AR in adrenergic (auto α2a‐AR) and non‐adrenergic neurons (hetero α2a‐AR) can go awry in neurological disorders such as anxiety and working memory deficits. In this project, we investigate whether auto α2a‐AR in sympathetic neurons use the same Gβγ as hetero α2a‐AR in other neuronal types. Gβγ specificity was determined by co‐IP Gβγ with α2a‐AR receptors and SNARE from synaptosomes, followed by mass spectrometry. We hypothesize that specific Gβγ's interact with activated auto‐ and hetero‐α2a‐ARs and inhibit exocytosis by interacting with SNARE. We have identified Gβ1, Gβ2, Gβ4, Gβ5, Gγ2, Gγ3, Gγ4, Gγ7, Gγ12, and Gγ13 which preferentially interact with the activated auto α2a‐AR and SNARE. We also expect to identify Gβ or Gγ's specific for hetero α2a‐AR. These studies may identify the Gβγ‐SNARE interaction as a new therapeutic target to modulate exocytosis in combination with drugs targeted to Gi/o‐coupled GPCRs. This work was supported by the National Institutes of Health (EY10291, MH101679, and T32).