Voltage-gated Ca(2+) influx and insulin secretion in human and mouse beta-cells are impaired by the mitochondrial Na(+)/Ca(2+) exchange inhibitor CGP-37157

Eur J Pharmacol. 2007 Dec 8;576(1-3):18-25. doi: 10.1016/j.ejphar.2007.07.055. Epub 2007 Aug 3.


Glucose-induced insulin release from pancreatic beta-cells relies largely on glucose metabolism and mitochondrial ATP synthesis. Inhibiting the mitochondrial Na(+)/Ca(2+) exchanger (mNCE) using 7-Chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157) has been suggested to enhance ATP synthesis and insulin secretion from rat islets by promoting mitochondrial Ca(2+) accumulation. In this study we examined the effects of CGP-37157 on human and mouse islet cells. Surprisingly, we found that insulin secretion from perifused islets was reduced by CGP-37157. Cytosolic Ca(2+) measurements revealed that CGP-37157 dose-dependently blocked glucose- and KCl-stimulated Ca(2+) signals in both human and mouse beta-cells. Conversely, CGP-37157 induced mitochondrial hyperpolarization, NAD(P)H rises, and triggered diazoxide- and nifedipine-sensitive cytosolic Ca(2+) transients in a subset of quiescent cells bathed in sub-stimulatory glucose, which is in accord with metabolic activation by the compound. Hence, while blocking mNCE with CGP-37157 may augment metabolism of human and mouse beta-cells, the propagation of metabolic signals is hampered by simultaneous inhibition of voltage-gated Ca(2+) influx, and ultimately insulin secretion. Efforts to use CGP-37157 or design related compounds for therapeutic purposes should take these competing effects into account.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / physiology*
  • Cells, Cultured
  • Clonazepam / analogs & derivatives*
  • Clonazepam / pharmacology
  • Glucose / pharmacology
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Potassium Chloride / pharmacology
  • Sodium-Calcium Exchanger / antagonists & inhibitors*
  • Sodium-Calcium Exchanger / physiology
  • Thiazepines / pharmacology*


  • Insulin
  • Sodium-Calcium Exchanger
  • Thiazepines
  • Clonazepam
  • Potassium Chloride
  • CGP 37157
  • Glucose
  • Calcium