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Hills, Claire E.; Younis, Mustafa Y. G.; Bennett, Jeanette; Siamantouras, Eleftherios; Liu, Kuo-Kang; Squires, Paul E.
Publisher: Karger
Languages: English
Types: Article
Subjects: QP
Identifiers:doi:10.1159/000341439
Background/Aims: The extracellular calcium-sensing receptor (CaR) is expressed in pancreatic β-cells where it is thought to facilitate cell-to-cell communication and augment insulin secretion. However, it is unknown how CaR activation improves β-cell function. Methods: Immunocytochemistry and western blotting confirmed the expression of CaR in MIN6 β-cell line. The calcimimetic R568 (1µM) was used to increase the affinity of the CaR and specifically activate the receptor at a physiologically appropriate extracellular calcium concentration. Incorporation of 5-bromo-2’-deoxyuridine (BrdU) was used to measure cell proliferation, whilst changes in non-nutrient-evoked cytosolic calcium were assessed using fura-2-microfluorimetry. AFM-single-cell-force spectroscopy related CaR-evoked changes in epithelial (E)-cadherin expression to improved functional tethering between coupled cells. Results: Activation of the CaR over 48hr doubled the expression of E-cadherin (206±41%) and increased L-type voltage-dependent calcium channel expression by 70% compared to control. These changes produced a 30% increase in cell-cell tethering and elevated the basal-to-peak amplitude of ATP (50µM) and tolbutamide (100µM)-evoked changes in cytosolic calcium. Activation of the receptor also increased PD98059 (1-100µM) and SU1498 (1-100µM)-dependent β-cell proliferation. Conclusion: Our data suggest that activation of the CaR increases E-cadherin mediated functional tethering between β-cells and increases expression of L-type VDCC and secretagogue-evoked changes in [Ca2+]i. These findings could explain how local changes in calcium, co-released with insulin, activate the CaR on neighbouring cells to help ensure efficient and appropriate secretory function.
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    • 10. Gray E, Squires PE, Muller D, Asare-Anane H, Cai Huang G, Amiel S, Persaud SJ, Jones PM: Activation of the extracellular calcium sensing receptor initiates insulin secretion from human islets of Langerhans: involvement of protein kinases. J Endocrinol 2006; 190: 711- 718.
    • 11. Squires PE: Non Ca2+-homeostatic functions of the extracellular Ca2+-sensing receptor (CaR) in endocrine tissues. J Endocrinology 2000; 165: 173-177.
    • 12. Hodgkin MN, Hills CE, Squires PE: The calcium-sensing receptor and insulin secretion: a role outside systemic control 15years on. J Endocrinol 2008; 199: 1-4.
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    • 15. Buchan AMJ, Squires PE, Ring M, Meloche RM: Mechanism of action of the calciumsensing receptor in human antral gastrin cells. Gastroenterology 2001; 120: 1128-1139.
    • 16. Squires PE, Meloche RM, Buchan AMJ: Bombesin-evoked gastrin release and calcium signaling in human antral G-cells in culture. Am J Physiol 1999; 276: G227-G237.
    • 17. Hofer AM, Curci S, Doble MA, Brown EM, Soybel DI: Intercellular communication mediated by the extracellular calcium-sensing receptor. Nature Cell Biol 2000; 2: 392-398.
    • 18. Hofer AM, Gerbino A, Caroppo R, Curci S: The extracellular calcium-sensing receptor and cell-cell signalling in epithelia. Cell Calcium 2004; 35: 297-306.
    • 19. Rogers GJ, Hodgkin MN, Squires PE: E-cadherin and cell adhesion: a role in architecture and function in the pancreatic islet. Cell Physiol Biochem 2007; 20: 987-994.
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