Na⁺/Ca²⁺ Exchange and the Plasma Membrane Ca²⁺-ATPase in β-Cell Function and Diabetes

Abstract

The rat pancreatic β-cell expresses two splice variants of the Na+/Ca²⁺ exchanger 1 (NCX1) and six splice variants of the plasma membrane Ca²⁺-ATPase (PMCA). In the β-cell, Na⁺/Ca²⁺ exchange displays a high capacity, contributes to both Ca²⁺ 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) Ca²⁺ 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 Ca²⁺ 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⁺/Ca²⁺ 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.