Splice variant-dependent regulation of beta-cell sodium-calcium exchange by acyl-coenzyme As

Mol Endocrinol. 2008 Oct;22(10):2293-306. doi: 10.1210/me.2008-0053. Epub 2008 Jul 17.


The sodium-calcium exchanger isoform 1 (NCX1) is intimately involved in the regulation of calcium (Ca(2+)) homeostasis in many tissues including excitation-secretion coupling in pancreatic beta-cells. Our group has previously found that intracellular long-chain acyl-coenzyme As (acyl CoAs) are potent regulators of the cardiac NCX1.1 splice variant. Despite this, little is known about the biophysical properties of beta-cell NCX1 splice variants and the effects of intracellular modulators on their important physiological function in health and disease. Here, we show that the forward-mode activity of beta-cell NCX1 splice variants is differentially modulated by acyl-CoAs and is dependent both upon the intrinsic biophysical properties of the particular NCX1 splice variant as well as the side chain length and degree of saturation of the acyl-CoA moiety. Notably, saturated long-chain acyl-CoAs increased both peak and total NCX1 activity, whereas polyunsaturated long-chain acyl-CoAs did not show this effect. Furthermore, we have identified the exon within the alternative splicing region that bestows sensitivity to acyl-CoAs. We conclude that the physiologically relevant forward-mode activity of NCX1 splice variants expressed in the pancreatic beta-cell are sensitive to acyl-CoAs of different saturation and alterations in intracellular acyl-CoA levels may ultimately lead to defects in Ca(2+)-mediated exocytosis and insulin secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / chemistry
  • Acyl Coenzyme A / metabolism*
  • Alternative Splicing*
  • Amino Acid Sequence
  • Animals
  • Calcium / metabolism*
  • Cell Line
  • Exocytosis / physiology
  • Humans
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Molecular Sequence Data
  • Palmitoyl Coenzyme A / chemistry
  • Palmitoyl Coenzyme A / metabolism
  • Patch-Clamp Techniques
  • Protein Conformation
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism*
  • Rats
  • Sequence Alignment
  • Sodium / metabolism*
  • Sodium-Calcium Exchanger / chemistry
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism*


  • Acyl Coenzyme A
  • Protein Isoforms
  • Sodium-Calcium Exchanger
  • sodium-calcium exchanger 1
  • Palmitoyl Coenzyme A
  • Sodium
  • Calcium