Inhibition of voltage‐gated Ca 2+ channels by sst4 stimulation is mediated by Gβγ and PKC activation

Healthcare System, Los Angeles, CA Stimulation of somatostatin subtype‐4 receptors (sst 4 ) in isolated retinal ganglion cells (RGCs) inhibits Ca 2+ channel current (I Ca ). Reducing intracellular Ca 2+ is known to be neuroprotective; thus, stimulating sst 4 may prevent RGC loss in trauma and disease. The aim of this study was to determine the signaling pathways involved in sst 4 stimulation leading to suppression of I Ca in RGCs. Isolated RGCs were prepared using a modified Thy‐1 immunopanning procedure. Electrophysiology experiments were performed using whole‐cell patch clamp to isolate I Ca . L‐803,087 (sst 4 agonist, L‐803) inhibited I Ca by 40.4% and reduced calcium conductance (2.1 vs. 1.4 nS; p<0.05). Pretreatment of cells with pertussis toxin did not prevent the action of L‐803 (34.7%). Pre‐pulse facilitation did not reverse the inhibitory effects of L‐803 on I Ca (11.4 vs. 9.7 %). However, pharmacologic inhibition of Gβγ prevented 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 (1 μM GFX, 34.3%; 5 μM GFX, 18.4%, p<0.05). This suggests that sst 4 stimulation modulates RGC Ca 2+ channels via Gβγ and PKC activation. Thus, modulating these signaling pathways may provide unique therapeutic targets to reduce intracellular Ca 2+ levels in RGCs. Support from CIHR‐NSHRF RPP, NIH.