Increase in [Ca²⁺]_i and Subsequent Insulin Release from βTC3-Cells with the L-Type Ca²⁺-Channel Activator, FPL 64176

Abstract

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 sugar^1,2. 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.