The 5-HT(1A) agonist 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) causes inhibition of caspase-3 and apoptosis via the extracellular signal-regulated kinases (ERK1/2) in hippocampal HN2-5 cells. Two 5-HT(1A) agonists, Repinotan hydrochloride (BAY x 3702) and 8-OH-DPAT, block caspase-3 activation and apoptosis caused by anoxia/reoxygenation and H(2)O(2) treatment. This is reversed upon transient expression of dominant negative Ras (N17Ras) and Raf-1 (Raf301), confirming the involvement of Ras and Raf-1 in this 5-HT(1A)-R-->ERK1/2-->caspase-3 pathway. A selective inhibitor of phospholipase Cbeta (PLCbeta) (U73122) but not a general protein kinase C (PKC) inhibitor (GFX) reversed the 5-HT(1A)-R-mediated ERK1/2 stimulation. However, both GFX and the PKCalpha and PKCbeta(1) inhibitor Gö6976 reversed the ERK1/2-mediated inhibition of caspase-3. ERK-dependent activation of only PKCalpha was observed in immunoprecipitates obtained from 5-HT(1A) agonist-treated HN2-5 cells. Finally, transient expression of kinase-negative PKCalpha eliminated the 8-OH-DPAT-evoked block on the H(2)O(2)-triggered caspase-3 stimulation, establishing PKCalpha as a link between ERK and caspase-3 (5-HT(1A)-R-->PLC-->ERK1/2-->PKCalpha-->caspase-3). Our results elucidate a novel yet general, neuroprotective pathway through which G protein-coupled receptors could cause inhibition of effector caspases, such as caspase-3.