| First Author | Park JC | Year | 2023 |
| Journal | Mol Cell | Volume | 83 |
| Issue | 14 | Pages | 2540-2558.e12 |
| PubMed ID | 37390816 | Mgi Jnum | J:338221 |
| Mgi Id | MGI:7510248 | Doi | 10.1016/j.molcel.2023.06.006 |
| Citation | Park JC, et al. (2023) Fine-tuning GPCR-mediated neuromodulation by biasing signaling through different G protein subunits. Mol Cell 83(14):2540-2558.e12 |
| abstractText | G-protein-coupled receptors (GPCRs) mediate neuromodulation through the activation of heterotrimeric G proteins (Galphabetagamma). Classical models depict that G protein activation leads to a one-to-one formation of Galpha-GTP and Gbetagamma species. Each of these species propagates signaling by independently acting on effectors, but the mechanisms by which response fidelity is ensured by coordinating Galpha and Gbetagamma responses remain unknown. Here, we reveal a paradigm of G protein regulation whereby the neuronal protein GINIP (Galpha inhibitory interacting protein) biases inhibitory GPCR responses to favor Gbetagamma over Galpha signaling. Tight binding of GINIP to Galphai-GTP precludes its association with effectors (adenylyl cyclase) and, simultaneously, with regulator-of-G-protein-signaling (RGS) proteins that accelerate deactivation. As a consequence, Galphai-GTP signaling is dampened, whereas Gbetagamma signaling is enhanced. We show that this mechanism is essential to prevent the imbalances of neurotransmission that underlie increased seizure susceptibility in mice. Our findings reveal an additional layer of regulation within a quintessential mechanism of signal transduction that sets the tone of neurotransmission. |
