Somatostatin receptor subtype 4 modulates L-type calcium channels via G beta gamma and PKC signaling in rat retinal ganglion cells

摘要

Somatostatin subtype-4 receptors (sst(4)) inhibit L-type calcium channel currents (I-Ca) in retinal ganglion cells (RGCs). Here we identify the signaling pathways involved in sst(4) stimulation leading to suppression of I-Ca in RGCs. Whole cell patch clamp recordings were made on isolated immunopanned RGCs using barium as a charge carrier to isolate I-Ca. Application of the selective sst(4) agonist, L-803 (10nM), reduced I-Ca by 41.2%. Pretreatment of cells with pertussis toxin (Gi/o inhibitor) did not prevent the action of L-803, which reduced I-Ca by 34.7%. To determine the involvement of G subunits after sst(4) activation, depolarizing pre-pulse facilitation paradigms were used to remove voltage-dependent inhibition of calcium channels. Pre-pulse facilitation did not reverse the inhibitory effects of L-803 on I-Ca (8.4vs. 8.8% reductions, ctrl vs. L-803); however, pharmacologic inhibition of G reduced I-Ca suppression by L-803 (23.0%, P < 0.05). Inhibition of PKC (GF109203X; GFX) showed a concentration-dependent effect in preventing the action of L-803 on I-Ca (1M GFX, 34.3%; 5M GFX, 14.6%, P < 0.05). When both PKC and G were inhibited, the effects of L-803 on I-Ca were blocked (1.8%, P < 0.05). These results suggest that sst(4) stimulation modulates RGC calcium channels via G and PKC activation. Since reducing intracellular Ca2+ is known to be neuroprotective in RGCs, modulating these sst(4) signaling pathways may provide insights to the discovery of unique therapeutic targets to reduce intracellular Ca2+ levels in RGCs.