Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different G-protein subunits

GPCRs mediate neuromodulation through activation of heterotrimeric G-proteins (Gαβγ). Classical models depict that G-protein activation leads to a one-to-one formation of Gα-GTP and Gβγ species. Each of these species propagates signaling by independently acting on effectors, but the mechanisms by which response fidelity is ensured by coordinating Gα and Gβγ responses remain unknown. Here, we reveal a paradigm of G-protein regulation whereby the neuronal protein GINIP biases inhibitory GPCR responses to favor Gβγ over Gα signaling. Tight binding of GINIP to Gαi-GTP precludes its association with effectors (adenylyl cyclase) and, simultaneously, with Regulator-of-G-protein-Signaling (RGS) proteins that accelerate deactivation. As a consequence, Gαi-GTP signaling is dampened whereas Gβγ signaling is enhanced. We show that this mechanism is essential to prevent imbalances of neurotransmission that underlie increased seizure susceptibility in vivo . Our findings reveal an additional layer of regulation within a quintessential mechanism of signal transduction that sets the tone of neurotransmission. ### Competing Interest Statement The authors have declared no competing interest.