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Glucose stimulates somatostatin secretion in pancreatic delta-cells by cAMP-dependent intracellular Ca-2+ release

Journal article
Authors G. Denwood
A. Tarasov
Albert Salehi
L. Vergari
R. Ramracheya
H. Takahashi
V. O. Nikolaev
S. Seino
F. Gribble
F. Reimann
Patrik Rorsman
Q. Zhang
Published in Journal of General Physiology
Volume 151
Issue 9
Pages 1094-1115
ISSN 0022-1295
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Physiology
Pages 1094-1115
Language en
Links dx.doi.org/10.1085/jgp.201912351
Keywords insulin granule dynamics, beta-cells, cyclic-amp, glucagon-secretion, cytoplasmic calcium, electrical-activity, ca2+ release, mouse islets, alpha-cells, c-epsilon, Physiology
Subject categories Physiology

Abstract

Somatostatin secretion from pancreatic islet delta-cells is stimulated by elevated glucose levels, but the underlying mechanisms have only partially been elucidated. Here we show that glucose-induced somatostatin secretion (GISS) involves both membrane potential-dependent and -independent pathways. Although glucose-induced electrical activity triggers somatostatin release, the sugar also stimulates GISS via a cAMP-dependent stimulation of CICR and exocytosis of somatostatin. The latter effect is more quantitatively important and in mouse islets depolarized by 70 mM extracellular K+, increasing glucose from 1 mM to 20 mM produced an similar to 3.5-fold stimulation of somatostatin secretion, an effect that was mimicked by the application of the adenylyl cyclase activator forskolin. Inhibiting cAMP-dependent pathways with PKI or ESI-05, which inhibit PKA and exchange protein directly activated by cAMP 2 (Epac2), respectively, reduced glucose/forskolin-induced somatostatin secretion. Ryanodine produced a similar effect that was not additive to that of the PKA or Epac2 inhibitors. Intracellular application of cAMP produced a concentration-dependent stimulation of somatostatin exocytosis and elevation of cytoplasmic Ca2+ ([Ca2+](i)). Both effects were inhibited by ESI-05 and thapsigargin (an inhibitor of SERCA). By contrast, inhibition of PKA suppressed delta-cell exocytosis without affecting [Ca2+](i) . Simultaneous recordings of electrical activity and [Ca2+](i) in delta-cells expressing the genetically encoded Ca2+ indicator GCaMP3 revealed that the majority of glucose-induced [Ca2+](i) spikes did not correlate with delta-cell electrical activity but instead reflected Cat' release from the ER. These spontaneous [Ca2+](i) spikes are resistant to PKI but sensitive to ESI-05 or thapsigargin. We propose that cAMP links an increase in plasma glucose to stimulation of somatostatin secretion by promoting CICR, thus evoking exocytosis of somatostatin-containing secretory vesicles in the delta-cell.

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