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Role of P2XR Channel Purinergic Signaling in Insulin Secretion: Implications in the Treatment of Diabetes
Author(s) -
Williams Clintoria Richards,
Contreras Juan L.,
Berecek Kathleen H.,
Schwiebert Erik M.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.991.10
Subject(s) - purinergic receptor , autocrine signalling , secretion , insulin , medicine , endocrinology , microbiology and biotechnology , purinergic signalling , biology , receptor , islet , signal transduction , biochemistry , adenosine receptor , agonist
Secretory defects in β‐cells of islets of Langerhans play a role in diabetes. It is accepted that ATP & zinc are co‐secreted with insulin. However, the physiological roles of these secreted molecules within islets are ill‐defined. We hypothesized that secreted ATP & zinc are autocrine purinergic signaling molecules that activate P2X purinergic receptor (P2XR) channels expressed by β‐cells to enhance glucose‐stimulated insulin secretion (GSIS). To test this postulate, ELISA, bioluminescence and fluorescence assays were used to examine insulin, ATP & zinc secretion, respectively, from β‐cells of islets. RT‐PCR, Western blot and immunofluorescence were used to investigate P2XR channel expression in islets and immortalized β‐cells. Findings confirmed that glucose stimulated release of the endogenous ligands for P2XR channels, ATP and zinc. When these secreted molecules were scavenged or chelated, respectively, GSIS was attenuated. In support, expression of multiple ATP‐gated & zinc‐modulated P2XR channel subtypes was observed in β‐cells. Antagonism of these receptors resulted in blunted GSIS. Furthermore, activation of β‐cell P2XR channels induced insulin secretion in a Ca 2+ ‐dependent manner. We conclude that secreted ATP & zinc have autocrine influence on insulin secretion that is mediated via P2XR channels and propose that the β‐cell P2XR channel signaling pathway is a therapeutic target in diabetes. S upported by an APS Porter Fellowship & a NRSA Predoctoral Fellowship.