title: Somatostatin receptor subtype 4 modulates L-type calcium channels via Gβγ and PKC signaling in rat retinal ganglion cells.
abstract: Somatostatin subtype-4 receptors (sst4) inhibit L-type calcium channel currents (ICa) in retinal ganglion cells (RGCs). Here we identify the signaling pathways involved in sst4 stimulation leading to suppression of ICa in RGCs. Whole cell patch clamp recordings were made on isolated immunopanned RGCs using barium as a charge carrier to isolate ICa. Application of the selective sst4 agonist, L-803 (10 nM), reduced ICa by 41.2%. Pretreatment of cells with pertussis toxin (Gi/o inhibitor) did not prevent the action of L-803, which reduced ICa by 34.7%. To determine the involvement of Gβγ subunits after sst4 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 ICa (8.4 vs. 8.8% reductions, ctrl vs. L-803); however, pharmacologic inhibition of Gβγ reduced ICa 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 ICa (1 μM GFX, 34.3%; 5 μM GFX, 14.6%, P < 0.05). When both PKC and Gβγ were inhibited, the effects of L-803 on ICa were blocked (1.8%, P < 0.05). These results suggest that sst4 stimulation modulates RGC calcium channels via Gβγ and PKC activation. Since reducing intracellular Ca(2+) is known to be neuroprotective in RGCs, modulating these sst4 signaling pathways may provide insights to the discovery of unique therapeutic targets to reduce intracellular Ca(2+) levels in RGCs.
authors.affiliation: a Department of Physiology & Biophysics ; Dalhousie University ; Halifax , NS , Canada.
authors.forename: Spring R
authors.initials: SR
authors.lastname: Farrell
authors.forename: Donald R
authors.initials: DR
authors.lastname: Rankin
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Brecha
authors.forename: Steven
authors.initials: S
authors.lastname: Barnes
mesh_terms: D000577:Amides / Q000494:pharmacology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D017481:Receptors, Somatostatin / Q000819:agonists / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000577:Amides; D020746:Calcium Channels, L-Type; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D007211:Indoles; C429628:L803087; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D011493:Protein Kinase C
keywords: 087; G-protein coupled receptor; GPCR; L-803; SRIF; Sst4