A highly energetic process couples calcium influx through L-type calcium channels to insulin secretion in pancreatic beta-cells

Am J Physiol Endocrinol Metab. 2009 Sep;297(3):E717-27. doi: 10.1152/ajpendo.00282.2009. Epub 2009 Jul 7.


Calcium (Ca(2+)) influx is required for the sustained secretion of insulin and is accompanied by a large rate of energy usage. We hypothesize that the energy usage reflects a process [Ca(2+)/metabolic coupling process (CMCP)] that couples Ca(2+) to insulin secretion by pancreatic islets. The aim of the study was to test this hypothesis by testing the effect of inhibiting candidate Ca(2+)-sensitive proteins proposed to play a critical role in the CMCP. The effects of the inhibitors on oxygen consumption rate (OCR), a reflection of ATP usage, and insulin secretion rate (ISR) were compared with those seen when L-type Ca(2+) channels were blocked with nimodipine. We reasoned that if a downstream Ca(2+)-regulated site was responsible for the OCR associated with the CMCP, then its inhibition should mimic the effect of nimodipine. Consistent with previous findings, nimodipine decreased glucose-stimulated OCR by 36% and cytosolic Ca(2+) by 46% and completely suppressed ISR in rat pancreatic islets. Inhibitors of three calmodulin-sensitive proteins (myosin light-chain kinase, calcineurin, and Ca(2+)/calmodulin-dependent protein kinase II) did not meet the criteria. In contrast, KN-62 severed the connection between Ca(2+) influx, OCR, and ISR without interfering with Ca(2+) influx. In the presence of nimodipine or KN-62, potentiators of ISR, acetylcholine, GLP-1, and arginine had little effect on insulin secretion, suggesting that the CMCP is also essential for the amplification of ISR. In conclusion, a KN-62-sensitive process directly mediates the effects of Ca(2+) influx via L-type Ca(2+) channels on OCR and ISR, supporting the essential role of the CMCP in mediating ISR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Animals
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / metabolism
  • Calcium Channels, L-Type / physiology*
  • Calcium Signaling / drug effects
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Cells, Cultured
  • Energy Metabolism / physiology*
  • Glucose / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / physiology
  • Models, Biological
  • Nimodipine / pharmacology
  • Oxidation-Reduction
  • Oxygen Consumption / drug effects
  • Oxygen Consumption / physiology
  • Rats
  • Rats, Sprague-Dawley


  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Insulin
  • Nimodipine
  • KN 62
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glucose
  • Calcium