Somatostatin participants in multiple physiological functions by activating the five distinct G-protein-coupled receptors (sst1-sst5). In this study, we investigated the effect of sst5 activation on outward K currents in acutely isolated rat retinal ganglion cells using whole-cell patch-clamp techniques. Extracellular application of L-817,818, a specific sst5 agonist, significantly reduced outward K currents which was mainly the 4-aminopyridine and glybenclamide sensitive current components, but not the tetraethylammonium-sensitive one. The L-817,818 effect was mediated by sst5 since the suppression was eliminated when intracellular dialysis of the G-protein inhibitor GDP-β-S or extracellular application of the sst5 antagonist BIM-23056. Intracellular phospholipase C/protein kinase C signaling pathway was involved in the L-817,818 effect because the L-817,818 effect on K currents was inhibited when rat retinal ganglion cells were pretreated with U73122 or chelerythrine chloride. However, L-817,818 persisted to reduce the K currents when cAMP/protein kinase A, calcium/calmodulin-dependent protein kinase II and mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathways were blocked respectively. These results suggest that sst5 activation suppresses 4-aminopyridine and glybenclamide-sensitive K currents in rat retinal ganglion cells by stimulating intracellular phospholipase C/protein kinase C signaling pathway, thereby regulating the rat retinal ganglion cell excitability.