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

Artikel i vetenskaplig tidskrift
Författare 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
Publicerad i Journal of General Physiology
Volym 151
Nummer/häfte 9
Sidor 1094-1115
ISSN 0022-1295
Publiceringsår 2019
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Sidor 1094-1115
Språk en
Länkar dx.doi.org/10.1085/jgp.201912351
Ämnesord insulin granule dynamics, beta-cells, cyclic-amp, glucagon-secretion, cytoplasmic calcium, electrical-activity, ca2+ release, mouse islets, alpha-cells, c-epsilon, Physiology
Ämneskategorier Fysiologi

Sammanfattning

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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