title: Growth hormone promotes Ca(2+)-induced Ca2+ release in insulin-secreting cells by ryanodine receptor tyrosine phosphorylation.
abstract: Elevation in cytoplasmic free Ca2+ concentration ([Ca2+]i) is a common mechanism in signaling events. An increased [Ca2+]i induced by GH, has been observed in relation to different cellular events. Little is known about the mechanism underlying the GH effect on Ca2+ handling. We have studied the molecular mechanisms underlying GH-induced rise in [Ca2+]i in BRIN-BD11 insulin-secreting cells. GH (500 ng/ml, 22 nm) induced a sustained increase in [Ca2+]i. The effect of GH on [Ca2+]i was prevented in the absence of extracellular Ca2+ and was inhibited by the ATP-sensitive K(+)-channel opener diazoxide and the voltage-dependent Ca(2+)-channel inhibitor nifedipine. However, GH failed to induce any changes in Ca2+ current and membrane potential, evaluated by patch-clamp recordings and by using voltage-sensitive dyes. When the intracellular Ca2+ pools had been depleted using the Ca(2+)-ATPase inhibitor thapsigargin, the effect of GH was inhibited. In addition, GH-stimulated rise in [Ca2+]i was completely abolished by ruthenium red, an inhibitor of mitochondrial Ca2+ transport, and caffeine. GH induced tyrosine phosphorylation of ryanodine receptors. The effect of GH on [Ca2+]i was completely blocked by the tyrosine kinase inhibitors genistein and lavendustin A. Interestingly, treatment of the cells with GH significantly enhanced K(+)-induced rise in [Ca2+]i. Hence, GH-stimulated rise in [Ca2+]i is dependent on extracellular Ca2+ and is mediated by Ca(2+)-induced Ca2+ release. This process is mediated by tyrosine phosphorylation of ryanodine receptors and may play a crucial role in physiological Ca2+ handling in insulin-secreting cells.
authors.affiliation: The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. Qimin.Zhang@sos.ki.se.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Martin
authors.initials: M
authors.lastname: Köhler
authors.forename: Shao-Nian
authors.initials: SN
authors.lastname: Yang
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Olof
authors.initials: O
authors.lastname: Larsson
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D013006:Growth Hormone / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007328:Insulin; D019837:Ryanodine Receptor Calcium Release Channel; D014443:Tyrosine; D019284:Thapsigargin; D013006:Growth Hormone; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D009543:Nifedipine; D003981:Diazoxide; D011188:Potassium; D002118:Calcium