A highly energetic process couples calcium influx through L-type calcium channels to insulin secretion in pancreatic beta-cells.
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.
Jung
Seung-Ryoung
SR
Dept. of Medicine, Diabetes and Obesity Center of Excellence, Univ. of Washington at South Lake Union, 815 Mercer St, Seattle, WA 98195-8055, USA.
Reed
Benjamin J
BJ
Sweet
Ian R
IR
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D009553:Nimodipine / Q000494:pharmacology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007328:Insulin; D009553:Nimodipine; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005947:Glucose; D002118:Calcium