The GABAB receptor mediates neuroprotection by coupling to G13

G protein–coupled receptors (GPCRs) activate various mitogen-activated protein kinase (MAPK) pathways to regulate critical cell functions. β-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 β-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, β-arrestin–independent, context-specific synergistic mechanisms of MAPK activation by G protein–mediated GPCR signaling.