Increase in [Ca2+]i and Subsequent Insulin Release from βTC3-Cells with the L-Type Ca2+-Channel Activator, FPL 64176
The regulation of calcium entry is central in the control of insulin secretion from the pancreatic β-cell. Glucose is the primary physiological stimulator of insulin secretion and a principal action of glucose is consequently to depolarize the β-cell by closing K+-channels sensitive to the ATP produced during metabolism of the sugar1,2. This will lead to membrane depolarization and activation of the voltage-dependent L-type Ca2+-channels leading to increase in intracellular calcium concentration, [Ca2+]i, and insulin secretion. Pharmacological important secretagogues such as sulphonylureas (e.g. glibenclamide) close the ATP-sensitive K+-channels leading to depolarization of the β-cell membrane, activation of voltage gated Ca2+-channels by opening the channels and initiation of repetitive action potentials. The resulting calcium influx increases the [Ca2+]i and thereby triggers insulin release. Compounds interfering with this process also regulate the insulin secretion and therefore the L-type Ca2+-channel might, like the ATP-sensitive K+-channel, be a suitable target for therapeutic intervention in treatment of Non-Insulin Dependent Diabetes Mellitus (NIDDM). The ligands for L-type Ca2+-channels can be divided into three categories: dihydropyridines, phenylalkylamines and benzothiazepines. Bay K 8644 has become the prototype for the class of dihydropyridines. Some of the dihydropyridines are chiral and resolution of these have revealed the (−)-enantiomers as potent activators, whereas the (+)-enantiomers are weak inactivators3. Analysis of the calcium current activation and deactivation kinetics shows that Bay K 8644 increases the mean open time while it leaves the mean closed times of the Ca2+-channel unchanged4.
KeywordsCholine Hepes Borate Verapamil Nifedipine
Unable to display preview. Download preview PDF.
- 4.Bechern, M. & Schramm, M.: Calcium-agonists. J. Mol. Cell Cardiol. 19 (Suppl. II) 63–75 (1987).Google Scholar
- 5.McKechnie, K., Killingback, P.G., Naya, I., O’Connor, S.E., Smith, G.W., Wattam, D.G., Wells, E., Whitehead, Y.M. & Williams, G.E.: Calcium channel activator properties in a novel non-dihydropyridine — FPL 64176. Br. J. Pharmacol. 98 673P (1989).Google Scholar
- 13.Kunze, D.L. & Rampe, D.: Characterization of the Effects of a New Ca2+ Channel Activator, FPL 64176, in GH3 Cells. Am. Soc. Pharm. and Exp. Ther. Molecular Pharm. 42 666–670 (1992).Google Scholar
- 14.Zheng, W., Rampe, D. & Triggle, D.J.: Pharmacological; Radioligand Binding, and Electrophysiological Characteristics of FPL 64176, a Novel Nondihydropyridine Ca2+ Channel Activatot in Cardiac and Vascular Preparations. Am. Soc. Pharm. and Exp. Ther. Molecular Pharm. 40 734-741.Google Scholar
- 15.Rampe, D. & Dage, R.C.: Functional Interactions between Two Ca2+ Channel Activators, (S)-Bay K 8644 and FPL 64176, in Smooth Muscle. Am. Soc. Pharm. and Exp. Ther. Molecular Pharm. 41 599–602 (1992).Google Scholar