1. Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release
- Author
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Denwood, G, Tarasov, A, Salehi, A, Vergari, E, Ramracheya, R, Takahashi, H, Nikolaev, V, Seino, S, Gribble, F, Reimann, F, Rorsman, P, and Zhang, Q
- Subjects
endocrine system ,Somatostatin-Secreting Cells ,Cell Membrane ,Colforsin ,Membrane Potentials ,Mice ,Glucose ,Adjuvants, Immunologic ,Gene Expression Regulation ,Cyclic AMP ,Animals ,Guanine Nucleotide Exchange Factors ,Thapsigargin ,Calcium ,Somatostatin ,Pancreas ,hormones, hormone substitutes, and hormone antagonists ,Research Articles ,Research Article - Abstract
The regulation of somatostatin secretion from islet δ-cells remains obscure. Denwood et al. show that glucose stimulates somatostatin secretion through effects on both δ-cell electrical activity and cAMP-dependent intracellular Ca2+ release., Somatostatin secretion from pancreatic islet δ-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 ∼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 δ-cell exocytosis without affecting [Ca2+]i. Simultaneous recordings of electrical activity and [Ca2+]i in δ-cells expressing the genetically encoded Ca2+ indicator GCaMP3 revealed that the majority of glucose-induced [Ca2+]i spikes did not correlate with δ-cell electrical activity but instead reflected Ca2+ 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 δ-cell.
- Published
- 2019