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Growth Hormone Promotes Ca²⁺-Induced Ca²⁺ Release in Insulin-Secreting Cells by Ryanodine Receptor Tyrosine Phosphorylation

The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet, S-171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Qimin Zhang, Karolinska Institutet, Research Center, Stockholm South Hospital, SE-11883 Stockholm, Sweden. E-mail: Qimin.Zhang{at}sos.ki.se.

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 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 [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 Ca²⁺-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.

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