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Originally published In Press as doi:10.1074/jbc.M001212200 on March 28, 2000

J. Biol. Chem., Vol. 275, Issue 28, 21033-21040, July 14, 2000
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Rapid Ca2+ Influx and Diacylglycerol Synthesis in Growth Hormone-mediated Islet beta -Cell Mitogenesis*

Åke SjöholmDagger §, Qimin ZhangDagger , Nils Welsh, Anders HanssonDagger , Olof LarssonDagger , Michael TallyDagger , and Per-Olof BerggrenDagger

From the Dagger  Department of Molecular Medicine, Endocrine and Diabetes Unit, Rolf Luft Center for Diabetes Research, Karolinska Institutet, Karolinska Hospital, S-171 76 Stockholm, Sweden and the  Department of Medical Cell Biology, University of Uppsala, S-751 23 Uppsala, Sweden

Growth hormone (GH) is an important mitogenic stimulus for the insulin-producing beta -cell. We investigated the effects of GH on Ca2+ handling and diacylglycerol (DAG) and cAMP formation in the beta -cell. GH elicited a rapid increase in the cytoplasmic free [Ca2+], which required extracellular Ca2+ and was also blocked by pertussis toxin or protein kinase C (PKC) inhibition. GH also elevated islet DAG content, which should lead to PKC activation. Pertussis toxin and PKC inhibitors obliterated the mitogenicity of GH, suggesting involvement of GTP-binding proteins. PKC activation stimulated beta -cell proliferation, and it also activated phospholipase D. Islet cAMP content was not elevated by GH. Addition of a specific protein kinase A antagonist failed to influence the mitogenicity of GH, whereas a stimulatory cAMP agonist stimulated beta -cell replication. We conclude that GH rapidly increases the beta -cell cytoplasmic free [Ca2+] and also evokes a similar increase in DAG content via a phosphatidylcholine-specific phospholipase C, but does not affect mitogen-activated protein kinases, phospholipase D, or the cAMP signaling pathway. This rise in DAG may be of importance in translation of the stimulatory signal of GH into a proliferative response by the beta -cell, which seems to occur through GTP-binding proteins and PKC-dependent mechanisms.

* This work was supported by Karolinska Institutet; Swedish Medical Research Council Grants 03X-12550, 12X-11564, 72P-12995, 19X-00034, 03X-09890, 03XS-12708, 03X-09891, and 12P-10151; the Swedish Diabetes Association; the Swedish Society of Medicine; the Nordic Insulin Foundation Committee; the Barndiabetesfonden; the Magnus Bergvall's Foundation; the Torsten and Ragnar Söderberg's Foundations; Novo-Nordisk Sweden Pharma AB; the Harald Jeansson's and Harald and Greta Jeansson's Foundations; the Tore Nilsson's Foundation for Medical Research; the Åke Wiberg's Foundation; the Syskonen Svensson's Fund; and the Fredrik and Inger Thuring's Foundation. Parts of this work have been published in abstract form (10).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Recipient of an Eli Lilly IEASD (European Association for the Study of Diabetes) Research Fellowship Award in Diabetes and Metabolism. To whom correspondence and reprint requests should be addressed: Dept. of Molecular Medicine, Endocrine and Diabetes Unit, Rolf Luft Center for Diabetes Research, Karolinska Inst., Karolinska Hospital (L6:01B), S-171 76 Stockholm, Sweden. Tel.: 46851775782/46705234057; Fax: 46851773658/468303458; E-mail: ake@enk.ks.se.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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