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

  • Janne Springborg
  • Jesper Gromada
  • Peter Madsen
  • Annemarie R. Vanning
  • Jannie Fuhlendorff
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 426)

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 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.

Keywords

Choline Hepes Borate Verapamil Nifedipine 

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Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Janne Springborg
    • 1
  • Jesper Gromada
    • 1
  • Peter Madsen
    • 1
  • Annemarie R. Vanning
    • 1
  • Jannie Fuhlendorff
    • 1
  1. 1.Novo Nordisk A/SNovo AlléBagsvaerdDenmark

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