Inhibition of β-cell sodium-calcium exchange enhances glucose-dependent elevations in cytoplasmic calcium and insulin secretion
KSC Hamming, D Soliman, NJ Webster, GJ Searle… - Diabetes, 2010 - Am Diabetes Assoc
KSC Hamming, D Soliman, NJ Webster, GJ Searle, LC Matemisz, DA Liknes, XQ Dai…
Diabetes, 2010•Am Diabetes AssocOBJECTIVE The sodium-calcium exchanger isoform 1 (NCX1) regulates cytoplasmic
calcium (Ca2+ c) 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. RESEARCH DESIGN AND METHODS The patch-clamp technique was …
calcium (Ca2+ c) 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. RESEARCH DESIGN AND METHODS The patch-clamp technique was …
OBJECTIVE
The sodium-calcium exchanger isoform 1 (NCX1) regulates cytoplasmic calcium (Ca2+c) 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.
RESEARCH 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. Ca2+ imaging and membrane capacitance were used to assess the effects of KB-R7943 on Ca2+c and insulin secretion in mouse and human β-cells and islets.
RESULTS
NCX1.3 and -1.7 calcium extrusion (forward-mode) activity was ∼16-fold more sensitive to KB-R7943 inhibition compared with cardiac NCX1.1 (IC50s = 2.9 and 2.4 vs. 43.0 μmol/l, respectively). In single mouse/human β-cells, 1 μmol/l KB-R7943 increased insulin granule exocytosis but was without effect on α-cell glucagon granule exocytosis. KB-R7943 also augmented sulfonylurea and glucose-stimulated Ca2+c levels and insulin secretion in mouse and human islets, although KB-R7943 was without effect under nonstimulated conditions.
CONCLUSIONS
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 Ca2+c and insulin secretion in mouse and human islets. Thus, we identify β-cell NCX1 splice variants as targets for the development of novel glucose-sensitive insulinotropic drugs for type 2 diabetes.
Am Diabetes Assoc