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This Article Full Text Full Text (PDF) All Versions of this Article: 297/3/E717    most recent 00282.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Jung, S.-R. Articles by Sweet, I. R. PubMed PubMed Citation Articles by Jung, S.-R. Articles by Sweet, I. R.

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

Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington at South Lake Union, Seattle, Washington

Submitted 30 April 2009 ; accepted in final form 2 July 2009

Calcium (Ca²⁺) 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 [Ca²⁺/metabolic coupling process (CMCP)] that couples Ca²⁺ to insulin secretion by pancreatic islets. The aim of the study was to test this hypothesis by testing the effect of inhibiting candidate Ca²⁺-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 Ca²⁺ channels were blocked with nimodipine. We reasoned that if a downstream Ca²⁺-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 Ca²⁺ by 46% and completely suppressed ISR in rat pancreatic islets. Inhibitors of three calmodulin-sensitive proteins (myosin light-chain kinase, calcineurin, and Ca²⁺/calmodulin-dependent protein kinase II) did not meet the criteria. In contrast, KN-62 severed the connection between Ca²⁺ influx, OCR, and ISR without interfering with Ca²⁺ 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 Ca²⁺ influx via L-type Ca²⁺ channels on OCR and ISR, supporting the essential role of the CMCP in mediating ISR.

oxygen consumption; calmodulin; islet; KN-62