Na(+)/Ca (2+) exchange and the plasma membrane Ca(2+)-ATPase in ß-cell function and diabetes.
Adv Exp Med Biol
; 961: 385-94, 2013.
Article
in En
| MEDLINE
| ID: mdl-23224897
ABSTRACT
The rat pancreatic ß-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 ß-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 ß-cell proliferation and ß-cell death by apoptosis. Interestingly, chronic exposure to cytokines or high free fatty acids concentration also induces ER Ca(2+) depletion and ß-cell death in diabetes. Loss of function studies shows, on the contrary, that heterozygous inactivation of NCX1 (Ncx1 ( +/- )) leads to an increase in ß-cell function (insulin production and release) and a fivefold increase in both ß-cell mass and proliferation. The mutation also increases ß-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 ß-cell function that are opposite to the major abnormalities seen in diabetes. In addition, the ß-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 ß-cell dysfunction in diabetes and following islet transplantation.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sodium-Calcium Exchanger
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Cell Proliferation
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Diabetes Mellitus
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Insulin-Secreting Cells
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Plasma Membrane Calcium-Transporting ATPases
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Endoplasmic Reticulum Stress
Limits:
Animals
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Humans
Language:
En
Journal:
Adv Exp Med Biol
Year:
2013
Document type:
Article
Affiliation country:
Belgium