Growth hormone promotes Ca2+-induced Ca2+ release in insulin-secreting cells by ryanodine receptor tyrosine phosphorylation

Qimin Zhang, Martin Köhler, Shao Nian Yang, Fan Zhang, Olof Larsson, Per Olof Berggren

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Elevation in cytoplasmic free Ca2+ concentration ([Ca 2+]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 [Ca 2+]i was prevented in the absence of extracellular Ca 2+ and was inhibited by the ATP-sensitive K+-channel opener diazoxide and the voltage-dependent Ca2+-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 Ca2+-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 [Ca 2+]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 [Ca 2+]i. Hence, GH-stimulated rise in [Ca2+] i is dependent on extracellular Ca2+ and is mediated by Ca2+-induced Ca2+ release. This process is mediated by tyrosine phosphorylation of ryanodine receptors and may play a crucial rale in physiological Ca2+ handling in insulin-secreting cells.

Original languageEnglish (US)
Pages (from-to)1658-1669
Number of pages12
JournalMolecular Endocrinology
Volume18
Issue number7
DOIs
StatePublished - Jul 1 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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