A stress response pathway in mice upregulates somatostatin level and transcription in pancreatic delta cells through Gs and β-arrestin 1

Abstract

Somatostatin secretion from islet delta cells plays an important role in regulating islet function and is tightly controlled by environmental changes. Activation of the adrenergic system promoted somatostatin secretion from islet delta cells; however, the role of the adrenergic system in regulating somatostatin content and transcription has not been defined. An imbalance between the somatostatin content and its secretion may cause dysfunctions in the islet delta cells. We have investigated the role of the adrenergic system in the modulation of somatostatin content and transcription in pancreatic delta cells and the detailed underlying mechanisms of this regulation. The stress hormone adrenaline (epinephrine), specific adrenergic agonists or specific adrenergic antagonists were applied to islets from either wild-type or specific adrenergic receptor knockout mice and pancreatic delta cell lines to investigate their effects on somatostatin content and transcription. The GloSensor assay, quantitative real-time PCR, western blots and the dual luciferase assay were used to monitor the cAMP level, somatostatin expression, activations of kinases and transcriptional factors. Arrb1 knockout mice, specific Creb or Pax6 mutations and specific kinase inhibitors were used to dissect the signalling pathway. Adrenaline and isoprenaline increased somatostatin content and transcription through the activation of β1-/β2-adrenergic receptors (β1-/β2ARs). The somatostatin content in β1AR ^−/− /β2AR ^−/− (Adrb1/Adrb2 knockout) mice was 50% lower than in β1AR ^+/+ /β2AR ^+/+ mice. Two parallel signalling pathways, Gs–cAMP–protein kinase A (PKA)–cAMP response element binding protein (CREB) and β-arrestin 1–extracellular signal-related kinase (ERK)–paired box protein 6 (PAX6), cooperatively regulated isoprenaline-induced somatostatin transcription. A stress pathway increased somatostatin content and transcription through β-adrenergic agonism. β-Arrestin1, ERK and PAX6 are important pancreatic delta cell regulators in addition to cAMP, PKA and CREB. Dysfunction of β-adrenergic agonism may impair pancreatic delta cell function.