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Heterologous desensitization of insulin secretion by GIP (glucose‐dependent insulinotropic peptide) in INS‐1 cells: the significance of Gα i2 and investigations on the mechanism involved
Author(s) -
Rucha A.,
Verspohl E. J.
Publication year - 2004
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/cbf.1134
Subject(s) - heterologous , secretion , mechanism (biology) , desensitization (medicine) , endocrinology , insulin , medicine , chemistry , peptide , biology , biochemistry , receptor , philosophy , epistemology , gene
Heterologous desensitization is a term that describes the observation that chronic exposure of a cell to an agonist attenuates its response to other agonists. To characterize the cellular mechanisms that might be responsible for heterologous desensitization in an insulin secretory cell system (INS‐1), we investigated the link between G‐protein α i2 level and insulin secretion as the biological effect after prolonged incubation with glucose‐dependent insulinotropic polypeptide (GIP). Persistent activation (8 h) of the GIP signalling pathway decreased the GLP (glucagon‐like peptide)‐1 dependent insulin secretion (specific radioimmunoassay) accompanied by an upregulation of G‐protein α i2 protein level to about 126% whereas G‐protein α i3 and α s protein levels remained unchanged (assessed by Western blots using specific antibodies). This was accompanied by similar changes in Gα i2 mRNA. By using either the CaM kinase II inhibitor KN‐62, the calcineurin inhibitor FK 506 or the protein kinase A (PKA) inhibitor Rp‐8‐Br‐cAMPS, the GIP‐mediated Gα i2 mRNA increase was fully reversed. Heterologous desensitization of GLP‐1‐dependent insulin secretion by pretreatment with GIP, however, was not inhibited by calcium/calmodulin‐dependent enzymes (using KN‐62 and FK 506), but only by suppressing the cAMP/PKA signalling pathway using Rp‐8‐Br‐cAMPS. The outcome is not disturbed by effects initiated by these compounds per se since an 8‐h preincubation of cells did not affect glucose‐induced insulin secretion. We, therefore, suggest that heterologous desensitization in INS‐1 cells may be mediated by Gα i2 changes but depend on the cAMP/PKA signalling pathway probably distant form the Gα i2 protein. Copyright © 2004 John Wiley & Sons, Ltd.