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dc.contributor.authorDenwood, Geoffrey
dc.contributor.authorTarasov, Andrei
dc.contributor.authorSalehi, Albert
dc.contributor.authorVergari, Elisa
dc.contributor.authorRamracheya, Reshma
dc.contributor.authorTakahashi, Harumi
dc.contributor.authorNikolaev, Viacheslav O
dc.contributor.authorSeino, Susumo
dc.contributor.authorGribble, Fiona
dc.contributor.authorReimann, Frank
dc.contributor.authorRorsman, Patrik
dc.contributor.authorZhang, Quan
dc.date.accessioned2019-10-22T00:09:44Z
dc.date.available2019-10-22T00:09:44Z
dc.date.issued2019-09-02
dc.identifier.citationDenwood , G , Tarasov , A , Salehi , A , Vergari , E , Ramracheya , R , Takahashi , H , Nikolaev , V O , Seino , S , Gribble , F , Reimann , F , Rorsman , P & Zhang , Q 2019 , ' Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ release ' , The Journal of general physiology , vol. 151 , no. 9 , pp. 1094-1115 . https://doi.org/10.1085/jgp.201912351
dc.identifier.issn0022-1295
dc.identifier.otherPURE: 17181059
dc.identifier.otherPURE UUID: d106e552-a708-4b95-8337-f4a27699a24d
dc.identifier.otherPubMed: 31358556
dc.identifier.otherScopus: 85071782107
dc.identifier.otherORCID: /0000-0002-8883-176X/work/63687441
dc.identifier.urihttp://hdl.handle.net/2299/21783
dc.description© 2019 Denwood et al.
dc.description.abstractSomatostatin 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.en
dc.format.extent22
dc.language.isoeng
dc.relation.ispartofThe Journal of general physiology
dc.rightsOpen
dc.titleGlucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular Ca2+ releaseen
dc.contributor.institutionSchool of Life and Medical Sciences
dc.description.statusPeer reviewed
dc.relation.schoolSchool of Life and Medical Sciences
dc.description.versiontypeFinal Published version
dcterms.dateAccepted2019-09-02
rioxxterms.versionVoR
rioxxterms.versionofrecordhttps://doi.org/10.1085/jgp.201912351
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue
herts.rights.accesstypeOpen


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