The ionic, electrical, and secretory effects of protein kinase C activation in mouse pancreatic B-cells: studies with a phorbol ester.
The phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) was used to study the effects of protein kinase C activation on stimulus-secretion coupling in mouse pancreatic B-cells. At a nonstimulatory concentration of glucose (3 mM), 100 nM TPA, but not 10 nM TPA, slightly and slowly increased insulin release and 45Ca2+ efflux and decreased 86Rb+ efflux, but did not affect the membrane potential of B-cells. At a threshold concentration of glucose (7 mM), 100 nM TPA markedly increased insulin release without triggering electrical activity in B-cells. At a stimulatory concentration of glucose (10 mM), TPA caused a dose-dependent irreversible increase in insulin release, 45Ca2+ efflux, and 86Rb+ efflux and slightly augmented islet cAMP levels. Omission of extracellular Ca2+ abolished the effects of 10 nM TPA and partially inhibited those of 100 nM TPA on insulin release and 45Ca2+ efflux. In contrast, their effect on 86Rb+ efflux was paradoxically augmented. Glucose-induced electrical activity in B-cells was only marginally affected by TPA; the duration of the slow waves with spikes was not modified, but a small shortening of the polarized intervals raised their frequency and slightly increased the overall activity. This increase was significant only with 10 nM TPA, whereas only 100 nM TPA brought about a minute increase in 45Ca2+ influx. These results thus show that TPA induces insulin release or potentiates glucose-induced insulin release without mimicking or amplifying the initial ionic and electrical signals triggered by glucose. They suggest that protein kinase C activation affects stimulus-secretion coupling by modulating intracellular and/or nonelectrogenic membrane events.
Bozem
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M
Nenquin
M
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Henquin
J C
JC
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism*; D011868:Radioisotopes; D012413:Rubidium / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D007328:Insulin; D011868:Radioisotopes; D011493:Protein Kinase C; D005947:Glucose; D012413:Rubidium; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium