Increase in [Ca2+]i and Subsequent Insulin Release from βTC3-Cells with the L-Type Ca2+-Channel Activator, FPL 64176
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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.
KeywordsInsulin Secretion Human Serum Albumin Insulin Release Intracellular Calcium Concentration Deactivation Kinetic
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