Current Status of PACAP as a Regulator of Insulin Secretion in Pancreatic Isletsa

Yada, Toshihiko; Sakurada, Masaya; Nakata, Masao; Ihida, Kaori; Yaekura, Kazuro; Shioda, Seiji; Kikuchi, Masatoshi

doi:10.1111/j.1749-6632.1996.tb17494.x

Cited by 19 publications

(12 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PACAP is effective only in the presence of glucose at concentrations above the threshold for insulin secretion, indicating that PACAP is a potentiator of glucoseinduced insulin release [25].…”

Section: Effects On Insulin Release and Signaling Mechanisms In -Cellsmentioning

confidence: 99%

PACAP in the Glucose and Energy Homeostasis: Physiological Role and Therapeutic Potential

Nakata¹,

Yada

2007

CPD

Self Cite

View full text Add to dashboard Cite

Pituitary adenylate cyclase activating polypeptide (PACAP) is a ubiquitous neuropeptide in the central and peripheral nervous systems. PACAP is also produced by pancreatic islet cells. PACAP regulates the glucose and energy metabolism at multiple processes in several tissues. At postprandial states, PACAP potentiates both insulin release from pancreatic beta-cells and insulin action in adipocytes, contributing to energy storage. At fasting states, PACAP on the one hand promotes feeding behavior by activating neuropeptide Y neurons in the hypothalamic feeding center, arcuate nucleus, and on the other hand stimulates secretion of catecholamine and glucagon and thereby induces lipolysis in adipocytes and glucose output from liver. Thus, PACAP plays an integrative role in the glucose and energy homeostasis. Dysfunction of expression, secretion and/or action of PACAP might be involved in the type 2 diabetes and metabolic syndrome. PACAP receptor subtype-specific agonists and/or antagonists are hopeful therapeutic agents.

show abstract

Section: Effects On Insulin Release and Signaling Mechanisms In -Cellsmentioning

confidence: 99%

PACAP in the Glucose and Energy Homeostasis: Physiological Role and Therapeutic Potential

Nakata¹,

Yada

2007

CPD

Self Cite

View full text Add to dashboard Cite

show abstract

“…glucose and GLP-1 (13,18,26). Furthermore, PACAP has been shown to increase [Ca 2ϩ ] i in a glucosedependent manner via opening of the VDCCs (1,33). To determine whether Ca 2ϩ played a role in PACAP-induced ERK1/2 activation, we used the VDCCs blocker, nifedipine.…”

Section: Pacap Via Pac 1 R Induces a Rapid And Transient Activation Omentioning

confidence: 99%

“…PACAP is expressed in islet parasympathetic nerve terminals and strongly potentiates insulin secretion in a glucose-dependent manner both in vitro (1)(2)(3)(4)(5) and in vivo in rodent (6) and humans (7). The physiological functions of PACAP are mediated by three receptor subtypes that belong to the class II G-protein-coupled receptors (GPCRs): PAC 1 , VPAC 1 and VPAC 2 receptors (Rs). PAC 1 R is selective for PACAP, whereas VPAC 1 R and VPAC 2 R bind to PACAP and Vasoactive Intestinal Peptide (VIP) with equal high affinity (8).…”

mentioning

confidence: 99%

β-Arrestin 1 Is Required for PAC1 Receptor-mediated Potentiation of Long-lasting ERK1/2 Activation by Glucose in Pancreatic β-Cells

Broca¹,

Quoyer²,

Costes

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

In pancreatic ␤-cells, the pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a potent insulin secretory effect via PAC 1 and VPAC receptors (Rs) through the G␣ s /cAMP/protein kinase A pathway. Here, we investigated the mechanisms linking PAC 1 R to ERK1/2 activation in INS-1E ␤-cells and pancreatic islets. PACAP caused a transient (5 min) increase in ERK1/2 phosphorylation via PAC 1 Rs and promoted nuclear translocation of a fraction of cytosolic p-ERK1/2. Both protein kinase A-and Src-dependent pathways mediated this transient ERK1/2 activation. Moreover, PACAP potentiated glucose-induced long-lasting ERK1/2 activation. Blocking Ca 2؉ influx abolished glucose-induced ERK1/2 activation and PACAP potentiating effect. Glucose stimulation during KCl depolarization showed that, in addition to the triggering signal (rise in cytosolic [Ca 2؉ ]), the amplifying pathway was also involved in glucose-induced sustained ERK1/2 activation and was required for PACAP potentiation. The finding that at 30 min glucoseinduced p-ERK1/2 was detected in both cytosol and nucleus while the potentiating effect of PACAP was only observed in the cytosol, suggested the involvement of the scaffold protein ␤-arrestin. Indeed, ␤-arrestin 1 (␤-arr1) depletion (in ␤-arr1 knockout mouse islets or in INS-1E cells by siRNA) completely abolished PACAP potentiation of long-lasting ERK1/2 activation by glucose. Finally, PACAP potentiated glucose-induced CREB transcriptional activity and IRS-2 mRNA expression mainly via the ERK1/2 signaling pathway, and likewise, ␤-arr1 depletion reduced the PACAP potentiating effect on IRS-2 expression. These results establish for the first time that PACAP potentiates glucose-induced long-lasting ERK1/2 activation via a ␤-arr1-dependent pathway and thus provide new insights concerning the mechanisms of PACAP and glucose actions in pancreatic ␤-cells.The neuropeptide, Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) 4 plays an important role in the regulation of pancreatic islet functions. PACAP is expressed in islet parasympathetic nerve terminals and strongly potentiates insulin secretion in a glucose-dependent manner both in vitro (1-5) and in vivo in rodent (6) and humans (7). The physiological functions of PACAP are mediated by three receptor subtypes that belong to the class II G-protein-coupled receptors (GPCRs): PAC 1 , VPAC 1 and VPAC 2 receptors (Rs). PAC 1 R is selective for PACAP, whereas VPAC 1 R and VPAC 2 R bind to PACAP and Vasoactive Intestinal Peptide (VIP) with equal high affinity (8). Class II GPCRs, which include also receptors for glucagon and the incretin glucagon-like peptide 1 (GLP-1), are coupled to the heterotrimeric G-protein Gs, which stimulates the adenylate cyclase (AC), (9). Besides its insulinotropic action, PACAP has been recently reported to exert long term beneficial effects on ␤-cell mass in various experimental mouse models of diabetes (10, 11). However, the receptor(s) and the mechanism(s) involved in these long term effects are yet unknown.Extracellu...

show abstract

“…In pancreatic ␤-cells, elevation of [Ca 2ϩ ] i occurs by release of Ca 2ϩ from intracellular pools such as the endoplasmic reticulum (ER), mitochondria, and secretory granules and/or by influx of extracellular Ca 2ϩ mainly through voltage-dependent calcium channels (VDCCs) (4,5). However, insulin secretion is induced by many secretagogues including glucose, sulfonylureas, and glucose-dependent potentiators such as glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and pituitary adenylate cyclase-activating peptide, all of which depend critically on Ca 2ϩ entering the pancreatic ␤-cells through the VDCCs, as these secretions are abolished by specific VDCC channel blockers (4,6,7).…”

mentioning

confidence: 99%

Essential Role of Ubiquitin-Proteasome System in Normal Regulation of Insulin Secretion

Kawaguchi

Minami

Nagashima

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

Insulin secretion from pancreatic ␤-cells occurs by sequential cellular processes, including glucose metabolism, electrical activity, Ca 2؉ entry, and regulated exocytosis. Abnormalities in any of these functions can impair insulin secretion. In the present study, we demonstrate that inhibition of proteasome activity severely reduces insulin secretion in the mouse pancreatic ␤-cell line MIN6-m9. Although no significant effects on glucose metabolism including ATP production were found in the presence of proteasome inhibitors, both glucose-and KCl-induced Ca 2؉ entry were drastically reduced. As Ca 2؉ -ionophore-induced insulin secretion was unaffected by proteasome inhibition, a defect in Ca 2؉ entry through voltage-dependent calcium channels (VDCCs) is the likely cause of the impaired insulin secretion. We found that the pore-forming ␣-subunit of VDCCs undergoes ubiquitination, which does not decrease but slightly increases expression of the ␣-subunit protein at the plasma membrane. However, electrophysiological analysis revealed that treatment with proteasome inhibitors results in a severe reduction in VDCC activity in MIN6-m9 cells, indicating that VDCC function is suppressed by proteasome inhibition. Furthermore, insulin secretion in isolated mouse pancreatic islets was also decreased by proteasome inhibition. These results demonstrate that the ubiquitin-proteasome system plays a critical role in insulin secretion by maintaining normal function of VDCCs.Insulin secretion from pancreatic ␤-cells is regulated by a variety of extracellular stimuli and intracellular signals (1-3). Regulated exocytosis of insulin-containing secretory granules is triggered by a rise in the intracellular (cytosolic) Ca 2ϩ concentration ([Ca 2ϩ ] i ) 3 (3). In pancreatic ␤-cells, elevation of [Ca 2ϩ ] i occurs by release of Ca 2ϩ from intracellular pools such as the endoplasmic reticulum (ER), mitochondria, and secretory granules and/or by influx of extracellular Ca 2ϩ mainly through voltage-dependent calcium channels (VDCCs) (4, 5). However, insulin secretion is induced by many secretagogues including glucose, sulfonylureas, and glucose-dependent potentiators such as glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and pituitary adenylate cyclase-activating peptide, all of which depend critically on Ca 2ϩ entering the pancreatic ␤-cells through the VDCCs, as these secretions are abolished by specific VDCC channel blockers (4, 6, 7).We previously established two different mouse pancreatic ␤-cell sublines from MIN6 cells, which facilitate study of the mechanisms of impaired insulin secretion (8). One of them is MIN6-m9, a model of normal ␤-cells having insulin secretory properties similar to those of pancreatic islets, and the other is MIN6-m14, which exhibits abnormalities in glucose metabolism, ATP-sensitive potassium (K ATP ) channels, and VDCCs that impair insulin secretion (8). In the course of comparing these sublines, we found that several genes involved in the ubiquitin-proteasome system are down-regula...

show abstract

Current Status of PACAP as a Regulator of Insulin Secretion in Pancreatic Isletsa

Cited by 19 publications

References 27 publications

PACAP in the Glucose and Energy Homeostasis: Physiological Role and Therapeutic Potential

PACAP in the Glucose and Energy Homeostasis: Physiological Role and Therapeutic Potential

β-Arrestin 1 Is Required for PAC1 Receptor-mediated Potentiation of Long-lasting ERK1/2 Activation by Glucose in Pancreatic β-Cells

Essential Role of Ubiquitin-Proteasome System in Normal Regulation of Insulin Secretion

Contact Info

Product

Resources

About