Rapid Ca2+ influx and diacylglycerol synthesis in growth hormone-mediated islet beta -cell mitogenesis.
Growth hormone (GH) is an important mitogenic stimulus for the insulin-producing beta-cell. We investigated the effects of GH on Ca(2+) handling and diacylglycerol (DAG) and cAMP formation in the beta-cell. GH elicited a rapid increase in the cytoplasmic free [Ca(2+)], which required extracellular Ca(2+) 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 [Ca(2+)] 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.
Sjöholm
A
A
Department of Molecular Medicine, Endocrine and Diabetes Unit, Rolf Luft Center for Diabetes Research, Karolinska Institutet, Karolinska Hospital, S-171 76 Stockholm, Sweden. ake@enk.ks.se
Zhang
Q
Q
Welsh
N
N
Hansson
A
A
Larsson
O
O
Tally
M
M
Berggren
P O
PO
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D004075:Diglycerides / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D005947:Glucose / Q000494:pharmacology; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D037342:Pertussis Toxin; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D004075:Diglycerides; D004791:Enzyme Inhibitors; D010566:Virulence Factors, Bordetella; D019382:Human Growth Hormone; D005576:Colforsin; D015240:Phorbol 12,13-Dibutyrate; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D005947:Glucose; D002118:Calcium