Activation of GABABR, the G protein–coupled receptor for the inhibitory neurotransmitter GABA, is thought to be neuroprotective through exclusive engagement of Gi/o. However, Wang et al. found that GABABR also engaged G13 to differentially activate the MAPK pathway kinase JNK. In cultured cerebellar granule neurons, this G13-mediated pathway increased the abundance of the postsynaptic scaffolding protein PSD95 and enhanced neuronal survival under low-potassium conditions. The authors further uncovered biological synergy between the two G protein–mediated pathways, with different kinetics in agonist responses. The findings reveal how GABA can mediate neuroprotection through multiple synergistic pathways that depend on distinct G proteins.