Molecular and Functional Characterization of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38)/Vasoactive Intestinal Polypeptide Receptors in Pancreatic β-Cells and Effects of PACAP-38 on Components of the Insulin Secretory System<sup>1</sup>

Borboni, P.; Porzio, Ottavia; Pierucci, Daniela; Cicconi, Simona; Magnaterra, R.; Federici, Massimo; Sesti, Giorgio; Lauro, Davide; D’Agata, Velia; Cavallaro, Sebastiano; Marlier, L.

doi:10.1210/endo.140.12.7208

Cited by 37 publications

(7 citation statements)

References 48 publications

(39 reference statements)

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“…In the current study, we show that PACAP interacts only with PAC 1 R to stimulate the MEK/ ERK1/2 cascade. In pancreatic ␤-cells, PAC 1 R is highly expressed, and binding studies indicate that PAC 1 R prevails over VPACR (41). The functional role of PAC 1 R has been confirmed in PAC 1 R-deficient mice, and we have shown that PAC 1 Rs are required for an optimal glucose-stimulated insulin secretion (40).…”

Section: Discussionsupporting

confidence: 57%

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

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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...

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Section: Discussionsupporting

confidence: 57%

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

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“…PACAP and PAC1 receptor expression can be altered in several types of tumours such as thyroid papillary carcinoma or testis cancer (Bardosi et al 2016;Nakamura et al 2014). Previous findings have shown messenger RNA of PAC1, VPAC1 and VPAC2 in insulinoma cells (Borboni et al 1999). It is also known that PACAP inhibits pancreas islet mass expansion and pancreatic islet density, which is associated with islet neogenesis in type II diabetes (Inoue et al 2013).…”

Section: Introductionmentioning

confidence: 94%

PACAP and PAC1 Receptor Expression in Human Insulinomas

Ferencz

Tóth

Kaszás

et al. 2021

Int J Pept Res Ther

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with widespread occurrence and diverse functions. PACAP binds to specific PAC1 and non-specific VPAC1/2 receptors. PACAP is considered as a growth factor, as it plays important roles during development and participates in reparative processes. Highest concentrations are found in the nervous system and endocrine glands, where several functions are known, including actions in tissue growth, differentiation and tumour development. Therefore, we have investigated expression of PACAP and its receptors in different tumours, including those of endocrine glands. We showed earlier that PACAP and PAC1 receptor staining intensity decreased in pancreatic ductal adenocarcinoma. In the present study we aimed to investigate alterations of PACAP and PAC1 receptor in human insulinoma and compared the immunostaining pattern with samples from chronic pancreatitis patients. We collected perioperative and histological data of patients who underwent operation because of insulinoma or chronic pancreatitis over a five-year-long period. Histology showed chronic pancreatitis with severe scar formation in pancreatitis patients, while tumour samples evidenced Grade 1 or 2 insulinoma. PACAP and PAC1 receptor expression was studied using immunohistochemistry. Staining intensity was very strong in the Langerhans islets of normal tissue and discernible staining was also observed in the exocrine pancreas. Immunostaining intensity for both PACAP and PAC1 receptor was markedly weaker in insulinoma samples, and disappeared from chronic pancreatitis samples except for intact islets. These findings show that PAC1 receptor/PACAP signalling is altered in insulinoma and this suggests a possible involvement of this system in tumour growth or differentiation.

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“…Maxadilan contains four cysteine residues, which form two disulfide bridges, one of which is located close to the N-terminus. Furthermore, it is known that the N-terminal residues of maxadilan are important for receptor binding 23, 29 . Therefore, it was thought likely that conjugation of DTPA to the N-terminus could influence the binding affinity.…”

Section: Discussionmentioning

confidence: 99%

“…As PAC1, VPAC1 and VPAC2 mRNAs were detected in a rat insulinoma cell line with PAC1 binding prevailing over that of VPAC1 and VPAC2 23 , the PAC1 receptor seemed to be a promising alternative for targeting insulinomas. The natural mammalian ligands at the PAC1 receptor are PACAP38 and the truncated form PACAP27.…”

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of PAC1 targeting with radiolabeled Maxadilan

Joosten

Brom

Schäfer

et al. 2017

Sci Rep

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There is an ongoing search for new tracers to optimize imaging of beta cell-derived tumors (insulinomas). The PAC1 receptor, expressed by insulinomas, can be used for targeting of these tumors. Here, we investigated whether radiolabeled maxadilan could be used for insulinoma imaging. Maxadilan was C- or N-terminally conjugated with DTPA (termed maxadilan-DPTA or DTPA-maxadilan respectively). BALB/c nude mice bearing subcutaneous INS-1 tumors were injected with either In-111-labeled maxadilan-DTPA or In-111-DTPA-maxadilan. Biodistribution studies were carried out at 1, 2 and 4 hours after injection and SPECT/CT imaging 1 and 4 hours after injection of maxadilan-DTPA-111In. Radiolabeling of maxadilan-DTPA (680 MBq/nmol) was more efficient than of DTPA-maxadilan (55 MBq/nmol). Conjugation with DTPA slightly reduced receptor binding affinity in vitro: IC50 values were 3.2, 21.0 and 21.0 nM for maxadilan, natIn-DTPA-maxadilan and maxadilan-DTPA-natIn respectively. Upon i.v. injection maxadilan-DTPA-111In accumulated specifically in INS-1 tumors (7.30 ± 1.87%ID/g) and in the pancreas (3.82 ± 0.22%ID/g). INS-1 tumors were clearly visualized by small animal SPECT/CT. In conclusion, this study showed that the high affinity of maxadilan to the PAC1 receptor was maintained after DTPA conjugation. Furthermore, radiolabeled maxadilan-DTPA accumulated specifically in INS-1 tumors and, therefore, may qualify as a useful tracer to image insulinomas.

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Molecular and Functional Characterization of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38)/Vasoactive Intestinal Polypeptide Receptors in Pancreatic β-Cells and Effects of PACAP-38 on Components of the Insulin Secretory System¹

Cited by 37 publications

References 48 publications

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

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

PACAP and PAC1 Receptor Expression in Human Insulinomas

Preclinical evaluation of PAC1 targeting with radiolabeled Maxadilan

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Molecular and Functional Characterization of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38)/Vasoactive Intestinal Polypeptide Receptors in Pancreatic β-Cells and Effects of PACAP-38 on Components of the Insulin Secretory System1

Cited by 37 publications

References 48 publications

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

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

PACAP and PAC1 Receptor Expression in Human Insulinomas

Preclinical evaluation of PAC1 targeting with radiolabeled Maxadilan

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Product

Resources

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Molecular and Functional Characterization of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP-38)/Vasoactive Intestinal Polypeptide Receptors in Pancreatic β-Cells and Effects of PACAP-38 on Components of the Insulin Secretory System¹