Na(+)/Ca (2+) exchange and the plasma membrane Ca(2+)-ATPase in β-cell function and diabetes

Adv Exp Med Biol. 2013:961:385-94. doi: 10.1007/978-1-4614-4756-6_33.

Abstract

The rat pancreatic β-cell expresses two splice variants of the Na+/Ca(2+) exchanger 1 (NCX1) and six splice variants of the plasma membrane Ca(2+)-ATPase (PMCA). In the β-cell, Na(+)/Ca(2+) exchange displays a high capacity, contributes to both Ca(2+) outflow and influx and participates to the control of insulin release. Gain of function studies show that overexpression of NCX1 or PMCA2 leads to endoplasmic reticulum (ER) Ca(2+) depletion with subsequent ER stress, decrease in β-cell proliferation and β-cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acids concentration also induces ER Ca(2+) depletion and β-cell death in diabetes. Loss of function studies shows, on the contrary, that heterozygous inactivation of NCX1 (Ncx1 ( +/- )) leads to an increase in β-cell function (insulin production and release) and a fivefold increase in both β-cell mass and proliferation. The mutation also increases β-cell resistance to hypoxia, and Ncx1 ( +/- ) islets show a four to seven times higher rate of diabetes cure than Ncx1 ( +/+ ) islets when transplanted in diabetic animals. Thus, downregulation of the Na(+)/Ca(2+) exchanger leads to various changes in β-cell function that are opposite to the major abnormalities seen in diabetes. In addition, the β-cell, which is an excitable cell, includes the mutually exclusive exon B in the alternative splicing region of NCX1, which confers a high sensitivity of its NCX splice variants (NCX1.3 & 1.7) to the inhibitory action of compounds like KB-R7943. This provides a unique model for the prevention and treatment of β-cell dysfunction in diabetes and following islet transplantation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Death
  • Cell Proliferation*
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / pathology
  • Diabetes Mellitus / surgery
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / physiology
  • Endoplasmic Reticulum Stress*
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Islets of Langerhans Transplantation
  • Mutation
  • Plasma Membrane Calcium-Transporting ATPases / genetics
  • Plasma Membrane Calcium-Transporting ATPases / metabolism*
  • Rats
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism*
  • Transplantation, Homologous

Substances

  • Sodium-Calcium Exchanger
  • sodium-calcium exchanger 1
  • Plasma Membrane Calcium-Transporting ATPases