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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation.
Cell. Signal. 51, 13-22 (2018)
Recently, a unimolecular Pi-agonist with activity at glucagon-like peptide 1 receptor (GLP-1R), glucose dependent insulinotropic receptor, and the glucagon receptor was reported to improve glycemic control in mice. Here, we defined the underlying molecular mechanisms of enhanced insulin secretion in murine pancreatic islets for a specific tri-agonist. The tii-agonist induced an increase in insulin secretion from murine islets compared to the respective mono-agonists. GLP-1R mainly signals via activation of the G alphas pathway, but inhibition of protein kinase A (H89) and exchange protein activation by cAMP (EPAC) (ESI-09) could not completely block insulin release induced by tri-agonist. Electrophysiological observations identified a strong increase of intracellular Ca2+ concentration and whole-cell currents induced by tri-agonist via transient receptor potential channels (TRPs). Although, EPAC activation mobilizes intracellular Ca2+ via TRPs, the TRPs blockers (La3+ and Ruthenium Red) had a larger inhibitory impact than ESI-09 on tri-agonist stimulatory effects. To test for other potential mechanisms, we blocked PLC activity (U73122) which reduced the superior effect of tri-agonist to induce insulin secretion, and partially inhibited the induced Ca2+ influx. This result suggests that the relative effect of tri-agonist on insulin secretion caused by GLP-1R agonism is mediated mainly via G alphas signaling and partially by activation of PLC. Therefore, the large portion of the increased intracellular Ca2+ concentration and the enhanced whole-cell currents induced by tri-agonist might be attributable to TRP channel activation resulting from signaling through multiple G-proteins. Here, we suggest that broadened intracellular signaling may account for the superior in vivo effects observed with tri-agonism.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Tri-agonist ; Signaling Cascade ; Pancreatic Islets ; Insulin Secretion ; G Proteins ; Trp Channels; Glucagon-like Peptide-1; Protein-coupled Receptors; Beta-cells; Glp-1 Receptor; Functional-characterization; Intracellular Loop; Ca2+ Channel; Glucose; Polypeptide; Obesity
ISSN (print) / ISBN
0898-6568
e-ISSN
0898-6568
Zeitschrift
Cellular Signalling
Quellenangaben
Band: 51,
Seiten: 13-22
Verlag
Elsevier
Verlagsort
360 Park Ave South, New York, Ny 10010-1710 Usa
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Diabetes and Obesity (IDO)