Enkephalins in human phaeochromocytomas: localization in immunoreactive, high molecular weight form to the soluble core of chromaffin granules

Rj, Parmer; Dt, O'Connor

doi:10.1097/00004872-198803000-00002

Cited by 15 publications

(4 citation statements)

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“…Catecholamine storage vesicles store and release other active peptides besides the chromogranins/secretogranins, including the potent vasoconstrictor neuropeptide Y (72) and the enkephalins (73); the genes encoding these other peptides might also harbor alleles that influence BP, but additional genetic loci were beyond the scope of this study. Although our blood pressure extreme groups were ascertained on a DBP criterion, recent evidence indicates that SBP is at least as important a risk factor for target organ damage; we plan future studies to explore the potential effect of CHGA polymorphism in isolated systolic hypertension.…”

Section: Discussionmentioning

confidence: 99%

Naturally Occurring Human Genetic Variation in the 3′-Untranslated Region of the Secretory Protein Chromogranin A Is Associated With Autonomic Blood Pressure Regulation and Hypertension in a Sex-Dependent Fashion

Chen

Rao

Rodríguez-Flores

et al. 2008

Journal of the American College of Cardiology

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Objective Determination whether common variation at the CHGA locus increases susceptibility to hypertension. Background Chromogranin A (CHGA) regulates catecholamine storage and release. Previously we systematically identified genetic variants across CHGA. Methods Dense genotyping across the CHGA locus in >1000 individuals with the most extreme BPs in the population, as well twin pairs with autonomic phenotypes. Characterizing function of a trait-associated 3'-UTR variant with transfected CHGA 3'-UTR/luciferase reporter plasmids. Results CHGA was overexpressed in patients with hypertension, especially hypertensive men, and CHGA predicted catecholamines. In individuals with extreme BPs, CHGA genetic variants predicted BP, especially in men, with a peak association occurred in the 3'-UTR at C+87T, accounting for up to ~12/~9 mmHg. The C+87T genotype predicted CHGA secretion in vivo, with the +87T allele (associated with lower BP) also diminishing plasma CHGA by ~10%. The C+87T 3'-UTR variant also predicted the BP response to environmental (cold) stress; the same allele (+87T) that diminished basal BP in the population also decreased the SBP response to stress by ~12 mmHg, and the response was smaller in women (by ~6 mmHg). In a chromaffin cell-transfected CHGA 3'-UTR/luciferase reporter plasmid, the +87T allele associated with lower BP also decreased reporter expression by ~30%. In cultured chromaffin cells, reducing endogenous Chga expression by si-RNA caused ~2/3 depletion of catecholamine storage vesicles. Conclusions Common variant C+87T in the CHGA 3'-UTR is a functional polymorphism causally associated with hypertension especially in men of the population, and propose steps ("intermediate phenotypes") whereby in sex-dependent fashion this genetic variant influences the ultimate disease trait. These observations suggest new molecular strategies to probe the pathophysiology, risk, and rational treatment of hypertension.

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Section: Discussionmentioning

confidence: 99%

Naturally Occurring Human Genetic Variation in the 3′-Untranslated Region of the Secretory Protein Chromogranin A Is Associated With Autonomic Blood Pressure Regulation and Hypertension in a Sex-Dependent Fashion

Chen

Rao

Rodríguez-Flores

et al. 2008

Journal of the American College of Cardiology

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“…Desensitization to catecholamine effects may contribute to under-diagnosis of the tumour in elderly patients. In addition to catecholamines, phaeochromocytomas also release a number of potentially vasoactive substances that may modify blood pressure or metabolism, such as calcitonin , serotonin, vasoactive intestinal polypeptide (Gozes et al 1983), enkephalins (Parmer & O'Connor 1988), atrial natriuretic factor and somatostatin.…”

Section: Pathophysiology and Complications Of Phaeochromocytomamentioning

confidence: 99%

Diseases of the adrenal medulla

2007

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The adrenal glands are vital in the organism's response to environmental stress. The outer cortex releases steroid hormones: glucocorticoids, mineralocorticoids and sex hormones, which are crucial to metabolism, inflammatory reactions and fluid homeostasis. The medulla is different developmentally, functionally and structurally. It co-releases catecholamines (primarily adrenaline and to some extent noradrenaline) as well as peptides by the all-or-none process of exocytosis from chromaffin granules, to aid in blood pressure and blood flow regulation, with regulated increments during the activation of the sympathetic nervous system. The co-released peptides function to regulate catecholamine release, blood vessel contraction and innate immune responses. Pathology within the adrenal medulla and the autonomic nervous system is primarily because of neoplasms. The most common tumour, called phaeochromocytoma when located in the adrenal medulla, originates from chromaffin cells and excretes catecholamines, but may be referred to as secreting paragangliomas when found in extra-adrenal chromaffin cells. Neoplasms, such as neuroblastomas and ganglioneuromas, may also be of neuronal lineage. We will also briefly discuss the catecholamine deficiency state. Keywordsadrenal; catecholamine; chromaffin; phaeochromocytoma Anatomy and physiologyThe adrenal medulla is the location of the majority of the organism's chromaffin cells, derived embryologically from neuroectoderm; ganglion cells and sustentacular cells are also found in the medulla. Chromaffin cells, which store catecholamines in secretory vesicles also known as chromaffin granules, are found in clusters (or nests) and in trabeculae, whereas the ganglion cells are found singly or in clusters interspersed among the chromaffin cells or in association with nerve fibres. The sustentacular cells, or support cells, are located at the periphery of clusters of chromaffin cells.The precursor chromaffin cells differentiate at the centre of the adrenal gland in response to the glucocorticoid cortisol. A minority of these cells also migrate to form paraganglia, collections of chromaffin cells on both sides of the aorta, the largest of which is primarily found at the origin of the inferior mesenteric artery or at the bifurcation of the aorta and is referred to as the organ of Zuckerkandl.Correspondence: D. T. O'Connor, Departments of Medicine and Pharmacology, Center for Human Genetics and Genomics (CHGG), University of California at San Diego, Skaggs (SSPPS) room 4256, 9500 Gilman Drive, La Jolla, CA 92093-0838, USA. E-mail: doconnor@ucsd.edu. Conflict of interestThere are no conflicts of interest for any of the authors for this paper. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe catecholamines are discharged from the chromaffin granules and sympathetic axons by the process of exocytosis, wherein all soluble components of the granule, including enzymes and chromogranins and bioactive peptides, are co-released into the extra...

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“…Catecholamine storage vesicles, subcellular organelles within chromaffin cells of the adrenal medulla and in sympathetic neurones [1], contain not only catecholamines but also ATP, calcium, peptides and proteins [2,3]; their contents are released in response to secretory signals by the process of exocytosis (all‐or‐none secretion) [4]. More generally, such vesicles in neuroendocrine cells [5] and neurones store and release the chromogranins or secretogranins (figure 1) (also known as ‘granins’), a paralogous group of acidic, soluble secretory proteins [6,7].…”

Section: Introduction: Catecholamine Storage Vesicles and The Chromogmentioning

confidence: 99%

Catecholamine storage vesicles and the metabolic syndrome: the role of the chromogranin A fragment pancreastatin

Zhang¹,

Rao²,

Wen³

et al. 2006

Diabetes Obesity Metabolism

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Chromogranins or secretogranins (granins), present in secretory granules of virtually all neuroendocrine cells and neurones, are structurally related proteins encoded by different genetic loci: chromogranins A and B, and secretogranins II through VI. Compelling evidence supports both intracellular and extracellular functions for this protein family. Within the cells of origin, a granulogenic or sorting role in the regulated pathway of hormone or neurotransmitter secretion has been documented, especially for chromogranin A (CHGA). Granins also function as pro-hormones, giving rise by proteolytic processing to an array of peptide fragments for which diverse autocrine, paracrine, and endocrine activities have been demonstrated. CHGA measurements yield insight into the pathogenesis of such human diseases as essential hypertension, in which deficiency of the catecholamine release-inhibitory CHGA fragment catestatin may trigger sympathoadrenal overactivity as an aetiologic culprit in the syndrome. The CHGA dysglycaemic fragment pancreastatin is functional in humans in vivo, affecting both carbohydrate (glucose) and lipid (fatty acid) metabolism. Pancreastatin is cleaved from CHGA in hormone storage granules in vivo, and its plasma concentration varies in human disease. The pancreastatin region of CHGA gives rise to three naturally occurring human variants, one of which (Gly297Ser) occurs in the functionally important carboxy-terminus of the peptide, and substantially increases the peptide's potency to inhibit cellular glucose uptake. These observations establish a role for pancreastatin in human intermediary metabolism and disease, and suggest that qualitative hereditary alterations in pancreastatin's primary structure may give rise to interindividual differences in glucose disposition.

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Enkephalins in human phaeochromocytomas: localization in immunoreactive, high molecular weight form to the soluble core of chromaffin granules

Cited by 15 publications

References 0 publications

Naturally Occurring Human Genetic Variation in the 3′-Untranslated Region of the Secretory Protein Chromogranin A Is Associated With Autonomic Blood Pressure Regulation and Hypertension in a Sex-Dependent Fashion

Naturally Occurring Human Genetic Variation in the 3′-Untranslated Region of the Secretory Protein Chromogranin A Is Associated With Autonomic Blood Pressure Regulation and Hypertension in a Sex-Dependent Fashion

Diseases of the adrenal medulla

Catecholamine storage vesicles and the metabolic syndrome: the role of the chromogranin A fragment pancreastatin

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