| First Author | Wang Y | Year | 2021 |
| Journal | Sci Signal | Volume | 14 |
| Issue | 705 | Pages | eaaz4112 |
| PubMed ID | 34665640 | Mgi Jnum | J:347329 |
| Mgi Id | MGI:7622133 | Doi | 10.1126/scisignal.aaz4112 |
| Citation | Wang Y, et al. (2021) The GABA(B) receptor mediates neuroprotection by coupling to G(13). Sci Signal 14(705):eaaz4112 |
| abstractText | G protein-coupled receptors (GPCRs) activate various mitogen-activated protein kinase (MAPK) pathways to regulate critical cell functions. beta-Arrestins mediate this mechanism for most GPCRs but not the GABA(B) receptor (GABA(B)R). When coupled to the G protein G(i/o), GABA(B)R phosphorylates the kinases ERK1 and ERK2. Here, we uncovered a distinct beta-arrestin-independent mechanism of MAPK pathway activation by GABA(B)R. We found that GABA(B)R also phosphorylated the kinase JNK downstream of activation of the small guanosine triphosphatases (GTPases) RhoA and Rac1 in primary mouse neurons. However, instead of G(i/o) proteins, activation of this RhoA/Rac1-JNK pathway was mediated by G(13). This pathway promoted the phosphorylation and accumulation of the postsynaptic scaffolding protein PSD95 and GABA(B)R-mediated neuroprotection in granule neurons. In addition, this pathway synergized with a previously reported GABA(B)R-mediated neuroprotection mediated by a G(i/o)-dependent mechanism. GABA(B)R agonists activated G(13) with slower kinetics and lower potency than with which they activated G(i/o). Our findings reveal distinct, beta-arrestin-independent, context-specific synergistic mechanisms of MAPK activation by G protein-mediated GPCR signaling. |
