Modulation of voltage-gated ion channels in rat retinal ganglion cells mediated by somatostatin receptor subtype 4

Somatostatin (somatotropin release-inhibiting factor [SRIF]) is known to modulate the excitability of retinal ganglion cells, but the membrane mechanisms responsible and the extent to which intracellular calcium signaling is affected have not been determined. We show that somatostatin receptor subtype 4 (sst₄) is expressed specifically in rat ganglion cells and that the generation of repetitive action potentials by isolated ganglion cells is reduced in the presence of L-803,087, a selective sst₄ agonist (10 nM). Under voltage clamp, L-803,087 increased outward K⁺ currents by 51.1 ± 13.1% at 0 mV and suppressed Ca²⁺ channel currents by 32.5 ± 9.4% at -10 mV in whole cell patch-clamped ganglion cells. The N-type Ca²⁺ channel blocker ω-conotoxin GVIA (CTX, 1 μM) reduced L-type Ca²⁺ current (I_Ca) in ganglion cells by 43.5 ± 7.2% at -10 mV, after which addition of L-803,087 further reduced I_Ca by 28.0 ± 16.0%. In contrast, ganglion cells treated first with nifedipine (NIF, 10 μM), which blocked 46.1 ± 3.5% of the control current at -10 mV, did not undergo any further reduction in I _Ca in the presence of L-803,087 (-3.5 ± 3.8% vs. NIF), showing that stimulation of sst₄ reduces Ca²⁺ influx through L-type Ca²⁺ channels. To assess the effects of sst₄ stimulation on intracellular Ca²⁺ levels ([Ca²⁺] _i) in ganglion cells, fura-2 was used to measure changes in [Ca ²⁺]_i in response to depolarization induced by elevated [K⁺]_o. [Ca²⁺]_i was increased to a lesser extent (86%) in the presence of L-803,087 compared with recordings made in the absence of the sst4 agonist and this effect was blocked by NIF (10 μM). Suppression of spiking and Ca²⁺ signaling via sst₄ may contribute to the reported neuroprotective actions of somatostatin and promote ganglion cell survival following ischemia and axonal trauma.