Inhibition of β-Cell Sodium-Calcium Exchange Enhances Glucose-Dependent Elevations in Gytoplasmic Calcium and Insulin Secretion

摘要

Objective-The sodium-calcium exchanger isoform 1 (NCX1) regulates cytoplasmic calcium (Ca_c~(2+)) required for insulin secretion in β-cells. NCX1 is alternatively spliced, resulting in the expression of splice variants in different tissues such as NCX1.3 and -1.7 in β-cells. As pharmacological inhibitors of NCX1 splice variants are in development, the pharmacological profile of β-cell NCX1.3 and -1.7 and the cellular effects of NCX1 inhibition were investigated.rnRESEARCH DESIGN AND METHODS-The patch-clamp technique was used to examine the pharmacological profile of the NCX1 inhibitor KB-R7943 on recombinant NCX1.3 and -1.7 activity. Ca~(2+) imaging and membrane capacitance were used to assess the effects of KB-R7943 on Ca_c~(2+) and insulin secretion in mouse and human β-cells and islets.rnRESULTS-NCX1.3 and -1.7 calcium extrusion (forward-mode) activity was ～ 16-fold more sensitive to KB-R7943 inhibition compared with cardiac NCX1.1 (IC_(50s) = 2.9 and 2.4 vs. 43.0 (xmol/1, respectively). In single mouse/human β-cells, 1 μmol/1 KB-R7943 increased insulin granule exocytosis but was without effect on α-cell glucagon granule exocytosis. KB-R7943 also augmented sulfonylurea and glucose-stimulated Ca_c~(2+) levels and insulin secretion in mouse and human islets, although KB-R7943 was without effect under nonstimulated conditions.rnCONCLUSIONS-Islet NCX1 splice variants display a markedly greater sensitivity to pharmacological inhibition than the cardiac NCX1.1 splice variant. NCX1 inhibition resulted in glucose-dependent increases in Ca_c~(2+) and insulin secretion in mouse and human islets. Thus, we identify 3-cell NCX1 splice variants as targets for the development of novel glucose-sensitive insulino-tropic drugs for type 2 diabetes.