Abstract
The rat pancreatic β cell expresses six splice variants of the plasma membrane Ca2+ ATPase (PMCA) and two splice variants of the Na/Ca exchanger 1 (NCX1). In the β cell, Na/Ca exchange displays a high capacity, contributes to both Ca2+ outflow and inflow, 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 fivefold 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, downregulation of the Na/Ca exchanger leads to various changes in β-cell function that are opposite to the major abnormalities seen in diabetes. Preliminary data indicate that heterozygous inactivation of PMCA2 leads to related though not completely similar results. These provide two unique models for the prevention and treatment of β-cell dysfunction in diabetes and following islet transplantation. 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 and 1.7) to the inhibitory action of compounds like KBR-7943. Hence, it is possible to develop NCX1 inhibitors acting preferentially on the β-cell to stimulate its proliferation in diabetes.
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Acknowledgments
The authors thank A. Van Praet, A. Iabkriman, and M-P. Berghmans (Laboratory of Pharmacology; ULB) for excellent technical support. This work has been supported by grants from the Belgian Fund for Scientific Research (FRSM 3.4593.04, 3.4527.08), the EFSD/Novo Nordisk Programme in Diabetes Research (2005/6), and JDRF (award 17-2011-650, USA).
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Herchuelz, A., Pachera, N. (2016). The Plasma Membrane Ca2+ ATPase and the Na/Ca Exchanger in β-cell Function and Diabetes. In: Chakraborti, S., Dhalla, N. (eds) Regulation of Ca2+-ATPases,V-ATPases and F-ATPases. Advances in Biochemistry in Health and Disease, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-24780-9_6
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DOI: https://doi.org/10.1007/978-3-319-24780-9_6
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