PuSH - Publikationsserver des Helmholtz Zentrums München: TGR5 activation promotes stimulus-secretion coupling of pancreatic -cells via a PKA-dependent pathway.

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Maczewsky, J.* ; Kaiser, J.* ; Gresch, A.* ; Gerst, F. ; Düfer, M.* ; Krippeit-Drews, P.* ; Drews, G.*

TGR5 activation promotes stimulus-secretion coupling of pancreatic -cells via a PKA-dependent pathway.

Diabetes 67, 324-336:db180315 (2018)

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The Takeda-G-protein-receptor-5 (TGR5) mediates physiological actions of bile acids. Since it was shown that TGR5 is expressed in pancreatic tissue, a direct TGR5 activation in -cells is currently postulated and discussed. The current study reveals that oleanolic acid (OLA) affects murine -cell function by TGR5 activation. Both a G(s) inhibitor and an inhibitor of adenylyl cyclase (AC) prevented stimulating effects of OLA. Accordingly, OLA augmented the intracellular cAMP concentration. OLA and two well-established TGR5 agonists, RG239 and tauroursodeoxycholic acid (TUDCA), acutely promoted stimulus-secretion coupling (SSC). OLA reduced K-ATP current and elevated current through Ca2+ channels. Accordingly, in mouse and human -cells, TGR5 ligands increased the cytosolic Ca2+ concentration by stimulating Ca2+ influx. Higher OLA concentrations evoked a dual reaction, probably due to activation of a counterregulating pathway. Protein kinase A (PKA) was identified as a downstream target of TGR5 activation. In contrast, inhibition of phospholipase C and phosphoinositide 3-kinase did not prevent stimulating effects of OLA. Involvement of exchange protein directly activated by cAMP 2 (Epac2) or farnesoid X receptor (FXR2) was ruled out by experiments with knockout mice. The proposed pathway was not influenced by local glucagon-like peptide 1 (GLP-1) secretion from -cells, shown by experiments with MIN6 cells, and a GLP-1 receptor antagonist. In summary, these data clearly demonstrate that activation of TGR5 in -cells stimulates insulin secretion via an AC/cAMP/PKA-dependent pathway, which is supposed to interfere with SSC by affecting K-ATP and Ca2+ currents and thus membrane potential.

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