Alterations of the Ca²⁺ signaling pathway in pancreatic beta-cells isolated from db/db mice.
10.1007/s13238-014-0075-7
- Author:
Kuo LIANG
1
;
Wen DU
;
Jingze LU
;
Fei LI
;
Lu YANG
;
Yanhong XUE
;
Bertil HILLE
;
Liangyi CHEN
Author Information
1. Department of General Surgery, XuanWu Hospital, Capital Medical University, Beijing, 100053, China.
- Publication Type:Journal Article
- MeSH:
Animals;
Calcium;
metabolism;
Calcium Signaling;
drug effects;
Cell Membrane Permeability;
drug effects;
Cells, Cultured;
Down-Regulation;
drug effects;
Endoplasmic Reticulum;
metabolism;
Glucose;
pharmacology;
Insulin-Secreting Cells;
cytology;
drug effects;
metabolism;
Mice;
Mice, Inbred C57BL;
Mice, Obese;
Potassium Chloride;
pharmacology;
Sarcoplasmic Reticulum Calcium-Transporting ATPases;
metabolism;
Sodium-Calcium Exchanger;
metabolism;
Thapsigargin;
pharmacology;
Up-Regulation;
drug effects
- From:
Protein & Cell
2014;5(10):783-794
- CountryChina
- Language:English
-
Abstract:
Upon glucose elevation, pancreatic beta-cells secrete insulin in a Ca(2+)-dependent manner. In diabetic animal models, different aspects of the calcium signaling pathway in beta-cells are altered, but there is no consensus regarding their relative contributions to the development of beta-cell dysfunction. In this study, we compared the increase in cytosolic Ca(2+) ([Ca(2+)]i) via Ca(2+) influx, Ca(2+) mobilization from endoplasmic reticulum (ER) calcium stores, and the removal of Ca(2+) via multiple mechanisms in beta-cells from both diabetic db/db mice and non-diabetic C57BL/6J mice. We refined our previous quantitative model to describe the slow [Ca(2+)]i recovery after depolarization in beta-cells from db/db mice. According to the model, the activity levels of the two subtypes of the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) pump, SERCA2 and SERCA3, were severely down-regulated in diabetic cells to 65% and 0% of the levels in normal cells. This down-regulation may lead to a reduction in the Ca(2+) concentration in the ER, a compensatory up-regulation of the plasma membrane Na(+)/Ca(2+) exchanger (NCX) and a reduction in depolarization-evoked Ca(2+) influx. As a result, the patterns of glucose-stimulated calcium oscillations were significantly different in db/db diabetic beta-cells compared with normal cells. Overall, quantifying the changes in the calcium signaling pathway in db/db diabetic beta-cells will aid in the development of a disease model that could provide insight into the adaptive transformations of beta-cell function during diabetes development.
