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Presynaptic receptors that are coupled to heterotrimeric G-proteins are found throughout the brain and are responsible for modulating synaptic transmission. At least 10 G-protein-coupled receptors (GPCRs) reduce transmission in hippocampal neurons. Additionally, hippocampal neurons express up to 17 different Gα, Gβ, and Gγ subunits, making for a striking array of possible heterotrimer compositions and GPCR–heterotrimer interactions. The identity of the Gα subunit is likely a critical determinant in coupling specificity between GPCRs and their molecular effectors mediating presynaptic inhibition. We studied the role of four Gαi/o subunits (Gαo1, Gαi1,Gαi2, and Gαi3) in mediating presynaptic inhibition in hippocampal neurons by expressing pertussis toxin-insensitive (PTx-ins) Gαi/o mutants. PTx treatment of these cells disrupts coupling of endogenous subunits, leaving only the mutant Gα subunits to couple with native GPCRs and βγ subunits. Successful rescue of presynaptic inhibition indicates that the expressed mutant Gα subunit can couple to the GPCR of interest. All four PTx-ins Gα subunits rescued presynaptic inhibition by adenosine A1 receptors. A PTx-ins Gα subunit also rescued adenosine A1-mediated inhibition of spontaneous vesicle fusion frequency. Of the remaining GPCRs tested, cannabinoid CB1, somatostatin, and GABAB receptors displayed an α subunit-dependent selectivity in binding to G-protein heterotrimers, whereas group III metabotropic glutamate receptor-mediated inhibition was not rescued by expression of any of the four PTx-ins Gα subunits. Differential coupling of G-protein α subunits may be a means of achieving specificity between different GPCRs and their molecular targets for mediating presynaptic inhibition.

G-Protein α Subunit Isoforms Couple Differentially to Receptors that Mediate Presynaptic Inhibition at Rat Hippocampal Synapses