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 (sst(4)) 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 sst(4) agonist (10 nM). Under voltage clamp, L-803,087 increased outward K(+) currents by 51.1 ± 13.1% at 0 mV and suppressed Ca(2+) channel currents by 32.5 ± 9.4% at -10 mV in whole cell patch-clamped ganglion cells. The N-type Ca(2+) channel blocker ω-conotoxin GVIA (CTX, 1 μM) reduced L-type Ca(2+) 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 sst(4) reduces Ca(2+) influx through L-type Ca(2+) channels. To assess the effects of sst(4) stimulation on intracellular Ca(2+) levels ([Ca(2+)](i)) in ganglion cells, fura-2 was used to measure changes in [Ca(2+)](i) in response to depolarization induced by elevated [K(+)](o). [Ca(2+)](i) was increased to a lesser extent (86%) in the presence of L-803,087 compared with recordings made in the absence of the sst(4) agonist and this effect was blocked by NIF (10 μM). Suppression of spiking and Ca(2+) signaling via sst(4) may contribute to the reported neuroprotective actions of somatostatin and promote ganglion cell survival following ischemia and axonal trauma.
Farrell
Spring R
SR
Dalhousie University, Department of Physiology and Biophysics, Halifax, Nova Scotia B3H 4H7.
Raymond
Iona D
ID
Foote
Michael
M
Brecha
Nicholas C
NC
Barnes
Steven
S
D000200:Action Potentials / Q000235:genetics / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D017481:Receptors, Somatostatin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000502:physiology*
D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4