par Herchuelz, André ;Pachera, Nathalie
Référence Neuroscience letters, 663, page (72-78)
Publication Publié, 2018-01
Article révisé par les pairs
Résumé : The rat pancreatic β-cell expresses 6 splice variants of the Plasma Membrane Ca2+-ATPase (PMCA) and two splice variants of the Na+/Ca2+ exchanger 1 (NCX1). 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 PMCA2 or NCX1 leads to endoplasmic reticulum (ER) Ca2+ depletion with subsequent ER stress, decrease in β-cell proliferation and β-cell death by apoptosis. Loss of function studies show, on the contrary, that heterozygous inactivation of NCX1 (Ncx1+/−) leads to an increase in β-cell function and a 5 fold increase in both β-cell mass and proliferation. The mutation also increases β-cell resistance to hypoxia, and Ncx1+/− islets show a 2–4 times higher rate of diabetes cure than Ncx1+/+ islets when transplanted in diabetic animals. Thus, down-regulation 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 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 KBR-7943. Heterozygous inactivation of PMCA2 leads to apparented, though not completely similar results.These provide 2 unique models for the prevention and treatment of β-cell dysfunction in diabetes and following islet transplantation.