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.
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.
Luciani
Dan S
DS
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
Ao
Peter
P
Hu
Xiaoke
X
Warnock
Garth L
GL
Johnson
James D
JD
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002478:Cells, Cultured; D002998:Clonazepam / Q000031:analogs & derivatives* / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors* / Q000502:physiology; D013841:Thiazepines / Q000494:pharmacology*
D007328:Insulin; D019831:Sodium-Calcium Exchanger; D013841:Thiazepines; D002998:Clonazepam; D011189:Potassium Chloride; C079032:CGP 37157; D005947:Glucose; D002118:Calcium