Role of PACAP in the physiology and pathology of the sympathoadrenal system

Ghzili, Hafida; Grumolato, Luca; Thouënnon, Erwan; Tanguy, Yannick; Turquier, Valérie; Vaudry, Hubert; Anouar, Youssef

doi:10.1016/j.yfrne.2007.10.001

Cited by 37 publications

(31 citation statements)

References 170 publications

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“…By contrast, PAC1-R expression was detected in all tumors analyzed, and its mRNA levels were w20-fold higher than those of VPAC1-R and VPAC2-R, suggesting that PAC1-R would be the predominant receptor for an autocrine effect of PACAP in pheochromocytoma. Accordingly, PAC1-R has been shown to mediate the effect of PACAP on catecholamine secretion in normal and tumoral sympathetic neurons (Taupenot et al 1998, Ghzili et al 2008. In addition, the prodifferentiating effects of PACAP are mediated through PAC1-R (Grumolato et al 2003b).…”

Section: Discussionmentioning

confidence: 99%

“…PACAP exerts its various effects through activation of PAC1, VPAC1, and VPAC2 receptors (Vaudry et al 2009). In adrenal medulla, PACAP regulates catecholamine and peptide biosynthesis and release via PAC1-R-activated signaling cascades (Guillemot et al 2006, Ghzili et al 2008. In human pheochromocytomas, PACAP and its receptors have been described, suggesting that this neuropeptide may affect tumoral chromaffin cell differentiation and activity (Isobe et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Thouënnon¹,

Aimar²,

Tanguy³

et al. 2010

Endocrine-Related Cancer

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Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Molecular pathways of malignant transformation remain poorly understood. Pheochromocytomas express various trophic peptides which may influence tumoral cell behavior. Here, we investigated the expression of trophic amidated peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM), and their receptors in benign and malignant pheochromocytomas in order to assess their potential role in chromaffin cell tumorigenesis and malignant transformation. PACAP, NPY, and AM are expressed in the majority of pheochromocytomas studied; NPY exhibiting the highest mRNA levels relative to reference genes. Although median gene expression or peptide levels were systematically lower in malignant compared to benign tumors, no statistically significant difference was found. Among all the receptors of these peptides that were analyzed, only the AM receptor RDC1 displayed a differential expression between benign and malignant pheochromocytomas. This receptor exhibited a fourfold higher expression in malignant than in benign tumors. AM and stromal cell-derived factor 1, which has also been described as a ligand for RDC1, increased the number of human pheochromocytoma cells in primary culture and exerted anti-apoptotic activity on rat pheochromocytoma PC12 cells. In addition, RDC1 gene silencing decreased the number of viable PC12 cells. This study shows the expression of several trophic peptides and their receptors in benign and malignant pheochromocytomas, and suggests that AM and its RDC1 receptor could be involved in chromaffin cell tumorigenesis through pro-survival effects. Therefore, AM and RDC1 may represent valuable targets for the treatment of malignant pheochromocytomas.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Thouënnon¹,

Aimar²,

Tanguy³

et al. 2010

Endocrine-Related Cancer

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“…The potent excitatory peptide PACAP is present in catecholaminergic bulbospinal neurons in the RVLM (10), in SPN in the spinal cord (12), in the adrenal medulla (24), and in chromaffin cell carcinomas (12). PACAP receptors are also present on blood vessels and in many other sites throughout the body (50,51).…”

Section: Perspectivesmentioning

confidence: 99%

Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat

Farnham

Inglott

Pilowsky

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Farnham MM, Inglott MA, Pilowsky PM. Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol 300: H214 -H222, 2011. First published October 15, 2010 doi:10.1152/ajpheart.00662.2010.-The rostral ventrolateral medulla contains presympathetic neurons that project monosynaptically to sympathetic preganglionic neurons (SPN) in the spinal cord and are essential for the tonic and reflex control of the cardiovascular system. SPN directly innervate the adrenal medulla and, via postganglionic axons, affect the heart, kidneys, and blood vessels to alter sympathetic outflow and hence blood pressure. Over 80% of bulbospinal, catecholaminergic (C1) neurons contain pituitary adenylate cyclaseactivating polypeptide (PACAP) mRNA. Activation of PACAP receptors with intrathecal infusion of PACAP-38 causes a robust, prolonged elevation in sympathetic tone. Given that a common feature of most forms of hypertension is elevated sympathetic tone, this study aimed to determine in the spontaneously hypertensive rat (SHR) and the Wistar Kyoto rat (normotensive control) 1) the proportion of C1 neurons containing PACAP mRNA and 2) responsiveness to intrathecal PACAP-38. We further investigated whether intrathecal infusion of the PACAP antagonist, PACAP(6 -38), reduces the hypertension in the SHR. The principal findings are that 1) the proportion of PACAP mRNA-containing C1 neurons is not different between normotensive and hypertensive rats, 2) intrathecal PACAP-38 causes a strain-dependent, sustained sympathoexcitation and tachycardia with variable effects on mean arterial pressure in normotensive and hypertensive rats, and 3) PACAP(6 -38) effectively attenuated the effects of intrathecal PACAP-38, but had no effect alone, on any baseline variables. This finding indicates that PACAP-38 is not tonically released in the spinal cord of rats. A role for PACAP in hypertension in conscious rats remains to be determined. sympathetic activity; spinal cord; pituitary adenylate cyclase-activating polypeptide THE ROSTRAL VENTROLATERAL MEDULLA (RVLM) is crucial for the tonic and reflex control of the cardiovascular system (see Refs. 15 and 43 for reviews). RVLM presympathetic neurons are commonly defined as being inhibited following baroreceptor activation and having a spinal axon (2, 28, 29). Neurochemically, 60 -80% of presympathetic neurons are C1 neurons (29,42,48,49), having all of the enzymes required for adrenaline synthesis. Presympathetic RVLM neurons project monosynaptically to sympathetic preganglionic neurons (SPN) in the intermediolateral (IML) cell column of the spinal cord (34,38). SPN, in turn, regulate the activity of the heart, kidneys, blood vessels, and adrenal chromaffin cells, thereby determining sympathetic outflow and ultimately blood pressure.Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory 38-amino-acid peptide originally identified in ovine hypothalamus (32) that also exists as a...

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“…2ϩ Mobilization-In sympathetic neurons including the sympathetic-like PC12 cells, PACAP exerts its actions through its PAC1 receptor coupled to G s and G q signaling proteins, which in turn activate multiple pathways including stimulation of several protein kinases and mobilization of Ca 2ϩ (10,25). In particular, MEK-dependent activation of the ERK1/2 MAP kinases and phosphatidylinositol 3-kinase (PI3K) play prominent roles in the neurotrophic effects exerted by PACAP in PC12 cells (26,27).…”

Section: Pacap Stimulates C-rel Activity Via Erk1/2 Kinases and Camentioning

confidence: 99%

Pituitary Adenylate Cyclase-activating Polypeptide (PACAP) Promotes Both Survival and Neuritogenesis in PC12 Cells through Activation of Nuclear Factor κB (NF-κB) Pathway

Manecka

Mahmood

Grumolato

et al. 2013

Journal of Biological Chemistry

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Background: PACAP induces neuronal differentiation in PC12 cells via multiple pathways that are not fully delineated. Results: PACAP elicits c-Rel nuclear translocation via ERK1/2 stimulation and Ca 2ϩ mobilization to induce cell survival and neuritogenesis. Conclusion: PACAP promotes PC12 cell survival and neuritogenesis by activating NF-B signaling. Significance: A novel molecular target of PACAP signaling during PC12 cell differentiation has been characterized.

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Role of PACAP in the physiology and pathology of the sympathoadrenal system

Cited by 37 publications

References 170 publications

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Expression of trophic amidated peptides and their receptors in benign and malignant pheochromocytomas: high expression of adrenomedullin RDC1 receptor and implication in tumoral cell survival

Intrathecal PACAP-38 causes increases in sympathetic nerve activity and heart rate but not blood pressure in the spontaneously hypertensive rat

Pituitary Adenylate Cyclase-activating Polypeptide (PACAP) Promotes Both Survival and Neuritogenesis in PC12 Cells through Activation of Nuclear Factor κB (NF-κB) Pathway

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