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- Title
Ghrelin Attenuates cAMP-PKA Signaling to Evoke Insulinostatic Cascade in Islet β-Cells.
- Authors
Dezaki, Katsuya; Damdindorj, Boldbaatar; Sone, Hideyuki; Dyachok, Oleg; Tengholm, Anders; Gylfe, Erik; Kurashina, Tomoyuki; Yoshida, Masashi; Kakei, Masafumi; Yada, Toshihiko
- Abstract
OBJECTIVE--Ghrelin reportedly restricts insulin release in islet β-cells via the Gα i2 subtype of G-proteins and thereby regulates glucose homeostasis. This study explored whether ghrelin regulates cAMP signaling and whether this regulation induces insulinostatic cascade in islet β-cells. RESEARCH DESIGN AND METHODS--Insulin release was measured in rat perfused pancreas and isolated islets and cAMP production in isolated islets. Cytosolic cAMP concentrations ([cAMP] i) were monitored in mouse MIN6 cells using evanescent-wave fluorescence imaging. In rat single β-cells, cytosolic protein kinase-A activity ([PKA]i) and Ca2+ concentration ([Ca-2+ ]i) were measured by DR-II and fura-2 microfluorometry, respectively, and whole cell currents by patch-clamp technique. RESULTS--Ghrelin suppressed glucose (8.3 mmol/L)-induced insulin release in rat perfused pancreas and isolated islets, and these effects of ghrelin were blunted in the presence of cAMP analogs or adenylate cyclase inhibitor. Glucose-induced cAMP production in isolated islets was attenuated by ghrelin and enhanced by ghrelin receptor antagonist and anti-ghrelin antiserum, which counteract endogenous islet-derived ghrelin. Ghrelin inhibited the glucose-induced [cAMP]i elevation and [PKA]i activation in MIN6 and rat β-cells, respectively. Furthermore, ghrelin potentiated voltage-dependent K+ (Kv) channel currents without altering Ca2+ channel currents and attenuated glucose-induced [Ca2+]i increases in rat β-cells in a PKA-dependent manner. CONCLUSIONS--Ghrelin directly interacts with islet β-cells to attenuate glucose-induced cAMP production and PKA activation, which lead to activation of Kv channels and suppression of glucose-induced [Ca2+]i increase and insulin release.
- Subjects
GHRELIN; GLUCOSE; G proteins; FLUORESCENCE; ADENOSINE monophosphate
- Publication
Diabetes, 2011, Vol 60, Issue 9, p2315
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db11-0368