PACAP stimulates insulin secretion by PAC1 receptor and ion channels in β-cells
Graphical abstract
Introduction
Pituitary adenylate cyclase-activating polypeptide (PACAP), a hypothalamic peptide, activates adenylate cyclase (AC) in rat pituitary cells [1]. PACAP is a member of the secretin-glucagon superfamily [2], including a 38-amino-acid form (PACAP38) and a shorter 27-amino-acid form (PACAP27). Chromatographic analyses have shown that the concentration of PACAP38 in extracted human pancreas is much higher than that of PACAP27 [3,4]. The peptide elicits its biological actions via regulating three types of class II G protein-coupled receptors (GPCRs): PAC1 receptor (PAC1-R), VPAC1 receptor (VPAC1-R), and VPAC2 receptor (VPAC2-R) [5]. PAC1-R has a distinct high affinity for PACAP. Study has shown that PACAP and its receptors are widely distributed in the central nervous system (CNS) and peripheral organs [1].
Previous study suggested that PACAP is a potential therapeutic target for diabetes and its complications [5]. It has been proposed that PACAP regulates postprandial glucose homeostasis and potentiates glucose-dependent insulin secretion from isolated rat islets [6,7]. However, the underlying mechanism of this action is still unknown. Pancreatic β-cells possess electrical excitability. Glucose-induced insulin secretion from β-cells is mediated by a series of electrophysiological activities, which result in exocytosis of insulin-containing granules [8]. Hence, we proposed that electrogenic events were involved in PACAP38-modulated glucose-stimulated insulin secretion through acting on G protein-coupled receptor and AC/PKA signaling pathways.
In this study, we used primary rat pancreatic islets and dispersed islet cells to explore the effects of PACAP38 on β-cell function, including insulin secretion, electrical activity, and intracellular Ca2+ concentration. Based on insulin secretion experiments and patch-clamp technology, we identified the cellular and molecular mechanisms whereby PACAP38 amplified glucose-induced insulin secretion.
Section snippets
Animals
Adult male Wistar rats, weighing 240–260 g, were purchased from Beijing Weitong Lihua experimental animal center. Rats were housed with pellet-type food and tap water under temperature (25 ± 2 °C) and humidity (55–60%) condition with a 12 h-light/darkness cycle. All experimental procedures involving animals described below were in accordance with the ethical guidelines for animal research at Shanxi Medical University and were approved by the Animal Care and Use Committee of Shanxi Medical
PACAP38 amplifies glucose-induced insulin secretion in rat pancreatic islets
To examine the effect of PACAP38 on insulin secretion, islets were stimulated with different doses of PACAP38 under 2.8 or 8.3 mM glucose. As shown in Fig. 1A, PACAP38 at various concentrations (0–100 nM) had no effect on insulin secretion under 2.8 mM glucose conditions. However, under conditions of 8.3 mM glucose, PACAP38 (10 and 100 nM) potentiated insulin secretion from isolated rat islets.
To confirm whether PACAP38-induced insulin secretion was glucose-dependent, islets were stimulated
Discussion
PACAP is a widely known potential insulinotropic neuropeptide [21,22]. It has been reported that administration of PACAP in vivo significantly enhanced plasma insulin levels in mice [23], pigs [24], and humans [25]. And studies have reported that PACAP amplified insulin secretion in a glucose-dependent manner [21,26]. Of note, we found that PACAP38 had no effect on insulin secretion at a low glucose concentration. PACAP38 dose-dependently augmented insulin secretion under high glucose
Declaration of interest
None.
Author contribution statement
Y Z, Y L and M L conceived and designed the study; M L, X Y, T B, Z L, T L and L C carried out the experiments; M L, X Y and T B contributed to analyze the data and interpret the results of the experiments; Y Z, Y L and M L wrote the manuscript; Y Z, Y L, M L and Y W revised the manuscript. All authors read and approved the final version.
Acknowledgments
This work was supported by NSFC (81670710; 81770776), Advanced Programs of Shanxi for the Returned Overseas Chinese Scholars (2016-97), Research Project Supported by Shanxi Scholarship Council of China (2017-053),FSKSC and 1331KSC.
References (44)
- et al.
Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells
Biochem. Biophys. Res. Commun.
(1989) - et al.
Geniposide acutely stimulates insulin secretion in pancreatic beta-cells by regulating GLP-1 receptor/cAMP signaling and ion channels
Mol. Cell. Endocrinol.
(2016) - et al.
Mechanisms of the amplifying pathway of insulin secretion in the beta cell
Pharmacol. Ther.
(2017) - et al.
Pituitary adenylate cyclase activating polypeptide is anextraordinarily potent intra-pancreatic regulator of insulin secretion fromislet beta-cells
J. Biol. Chem.
(1994) - et al.
Vasoactive intestinal polypeptide and pituitary adenylate cyclase activating polypeptide: effects on insulin release in isolated mouse islets in relation to metabolic status and age
Neuropeptides
(2006) - et al.
VPAC and PAC receptors: from ligands to function
Pharmacol. Ther.
(2009) - et al.
Kv2.1 ablation alters glucose-induced islet electrical activity, enhancing insulin secretion
Cell Metab.
(2007) - et al.
Inhibition of Kv2.1 voltage-dependent K+ channels in pancreatic beta-cells enhances glucose-dependent insulin secretion
J. Biol. Chem.
(2002) - et al.
Expression and function of pancreatic beta-cell delayed rectifier K+ channels. Role in stimulus-secretion coupling
J. Biol. Chem.
(1996) - et al.
Evidence for contribution by increased cytoplasmic Na+ to the insulinotropic action of PACAP38 in HIT-T15 cells
J. Biol. Chem.
(1998)
Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions
Pharmacol. Rev.
Pituitary adenylate cyclase-activating polypeptide stimulates insulin and glucagon secretion in humans
J. Clin. Endocrinol. Metab.
Role of pituitary adenylate cyclase-activating polypeptide in the pancreatic endocrine system
Ann. N. Y. Acad. Sci.
Emerging role of PACAP as a new potential therapeutic target in major diabetes complications
Int. J. Endocrinol.
Pituitary adenylate cyclase-activating polypeptide receptors mediating insulin secretion in rodent pancreatic islets are coupled to adenylate cyclase but not to PLC
Endocrinology
PACAP in the glucose and energy homeostasis: physiological role and therapeutic potential
Curr. Pharm. Des.
Voltage-dependent K(+) channels in pancreatic beta cells: role, regulation and potential as therapeutic targets
Diabetologia
Voltage-gated and resting membrane currents recorded from B-cells in intact mouse pancreatic islets
J. Physiol. Biochem.
Inhibition of voltage-dependent potassium channels mediates cAMP-potentiated insulin secretion in rat pancreatic β cells
Islets
International Union of Pharmacology. XVIII. Nomenclature of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide
Pharmacol. Rev.
The neuropeptide pituitary adenylate cyclaseactivating polypeptide and islet function
Diabetes
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