Possible involvement of A2A and A3 receptors in modulation of insulin secretion and β-cell survival in mouse pancreatic islets

Adenosine A(1), A(2)A, A(2)B and A(3) receptor mRNAs were found to be expressed in mouse pancreatic islets and Beta-TC6 cells but their physiological or pharmacological actions are not fully clarified. We showed that adenosine (1001 mu M) augmented insulin secretion by islets in the presence of either normal (5.5 mM) or a high concentration of glucose (20 mM). The augmentation of insulin secretion in the presence of high glucose was blocked by an A(2)A antagonist, but not by A(2B) and A(3) antagonists, while an A(1) antagonist potentiated the adenosine effect. An adenosine analogue 5'-N-ethylcarboxamidoadenosine (NECA) as well as A(2)A and A(3) receptor agonists also produced stimulation. On the other hand, an A(3) agonist markedly reduced Beta-TC6 cell proliferation and the islet cell viability, while adenosine and NECA did not. The effect of A(3) agonist was partially blocked by the A(3) antagonist. In addition, treatment with the A(3) agonist produced a small but significant extent of apoptosis in Beta-TC6 cells as judged by terminal transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) assay. These results combined together suggested that like the Al receptor, activation of A(2)A receptors by adenosine results in augmented insulin secretion, while the A(3) receptor is involved in modulation of the survival of pancreatic beta-cells. (C) 2013 Published by Elsevier Inc.