Influence of a tumor-promoting phorbol ester on the electrical response of B-cells to glucose and glyburide.
The tumor-promoting phorbol ester, 12-0-tetradecanoylphorbol-13-acetate (TPA), enhances the secretory responses of pancreatic islet cells to glucose and a hypoglycemic sulfonylurea. The influence of TPA on the electrical activity induced by glucose or the sulfonylurea, glyburide, was assessed to determine whether TPA altered the conductances of the K+ and Ca2+ channels subserving depolarization and spike generation. TPA, 0.2 microM, did not alter the membrane potential obtained with 0-5.6 mM glucose. With 7.0, 8.4, and 11.0 mM glucose, TPA increased the duration of the active phase of oscillatory spike activity more than 2-fold. Upon withdrawal of glucose or glucose plus TPA, the cells hyperpolarized and spike activity ceased. In cells not exposed to TPA, the subsequent addition of 10 nM glyburide resulted in slow depolarization after 10-13 min and occurred at a rate of 1.2 +/- 0.2 mV/min. In cells preexposed to TPA, depolarization commenced by 4-8 min and occurred at a rate of 3.2 +/- 0.4 mV/min. The magnitude of depolarization was 15-20 mV with both conditions. Small amplitude spikes appeared during depolarization. After depolarization, the onset of high amplitude spikes appeared sooner in TPA-treated B-cells and occurred 2.6 times more frequently during the first 6.5 min after depolarization than in B-cells not exposed to TPA. A stable pattern of spike generation was achieved twice as fast in TPA-treated cells. TPA enhancement of glucose- and glyburide-induced spike activity suggests that the insulinotropic action of TPA is mediated by augmenting the influx of Ca2+ into the B-cell via voltage-sensitive Ca2+ channels.
D000818:Animals; D004553:Electric Conductivity / Q000187:drug effects; D005071:Evoked Potentials / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008808:Mice, Inbred CBA; D010704:Phorbols / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D010704:Phorbols; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate; D005905:Glyburide