The KATP channel is critical for calcium sequestration into non-ER compartments in mouse pancreatic beta cells

K-ATP channel activity influences beta cell Ca2+ homeostasis by regulating Ca2+ influx through L-type Ca2+ channels. The present paper demonstrates that loss of K-ATP channel activity due to pharmacologic or genetic ablation affects Ca2+ storage in intracellular organelles. ATP depletion, by the mitochondrial inhibitor FCCP, led to Ca2+ release from the endoplasmic reticulum (ER) of wildtype beta cells. Blockade of ER Ca2+ ATPases by cyclopiazonic acid abolished the FCCP-induced Ca2+ transient. In beta cells treated with K-ATP channel inhibitors FCCP elicited a significantly larger Ca2+ transient. Cyclopiazonic acid did not abolish this Ca2+ transient suggesting that non-ER compartments are recruited as additional Ca2+ stores in beta cells lacking K-ATP channel activity. Genetic ablation of K-ATP channels in SUR1KO mice produced identical results. In INS-1 cells transfected with a mitochondrial-targeted Ca2+- sensitive fluorescence dye (ratiometric pericam) the increase in mitochondrial Ca2+ evoked by tolbutamide was 5-fold larger compared to 15 mM glucose. These data show that genetic or pharmacologic ablation of K-ATP channel activity conveys Ca2+ release from a non-ER store. Based on the sensitivity to FCCP and the property of tolbutamide to increase mitochondrial Ca2+ it is suggested that mitochondria are the recruited store. The change in Ca2+ sequestration in beta cells treated with insulinotropic antidiabetics may have implications for beta cell survival and the therapeutic use of these drugs. Copyright (c) 2007 S. Karger AG, Basel.