title: Na(+)/Ca (2+) exchange and the plasma membrane Ca(2+)-ATPase in β-cell function and diabetes.
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.
authors.affiliation: Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, Brussels, Belgium. herchu@ulb.ac.be
authors.forename: André
authors.initials: A
authors.lastname: Herchuelz
authors.forename: Evrard
authors.initials: E
authors.lastname: Nguidjoe
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pachera
mesh_terms: D000818:Animals; D016923:Cell Death; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D009154:Mutation; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D053499:Plasma Membrane Calcium-Transporting ATPases