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Sushil K. Mahata - One of the best experts on this subject based on the ideXlab platform.

  • The anti-inflammatory peptide Catestatin blocks chemotaxis
    2020
    Co-Authors: Elke M. Muntjewerff, Kristel Parv, Sushil K. Mahata, Mia Phillipson, Gustaf Christoffersson, Geert Van Den Bogaart
    Abstract:

    AbstractIncreased levels of the anti-inflammatory peptide Catestatin (CST), a cleavage product of the pro-hormone chromogranin A, correlates with less severe outcomes in hypertension, colitis and diabetes. However, it is unknown how CST reduces the infiltration of monocytes and macrophages in inflamed tissues. Here, we report that CST blocks leukocyte migration towards inflammatory chemokines. By in vitro and in vivo migration assays, we show that although CST itself is weakly chemotactic, it blocks migration of monocytes and granulocytes to inflammatory attracting factor CC-chemokine ligand 2 (CCL2) and macrophage inflammatory protein 2 (MIP-2). Moreover, it directs CX3CR1+ macrophages away from pancreatic islets. These findings support the emerging notion that CST is a key anti-inflammatory modulator.

  • Catestatin as a Target for Treatment of Inflammatory Diseases
    Frontiers in immunology, 2018
    Co-Authors: Elke M. Muntjewerff, Sushil K. Mahata, Gina Dunkel, Mara J. T. Nicolasen, Geert Van Den Bogaart
    Abstract:

    It is increasingly clear that inflammatory diseases and cancers are influenced by cleavage products of the pro-hormone chromogranin A (CgA), such as the 21-amino acids long Catestatin (CST). The goal of this review is to provide an overview of the anti-inflammatory effects of CST and its mechanism of action. We discuss evidence proving that CST and its precursor CgA are crucial for maintaining metabolic and immune homeostasis. CST could reduce inflammation in various mouse models for diabetes, colitis and atherosclerosis. In these mouse models, CST treatment resulted in less infiltration of immune cells in affected tissues, although in vitro monocyte migration was increased by CST. Both in vivo and in vitro, CST can shift macrophage differentiation from a pro- to an anti-inflammatory phenotype. Thus, the concept is emerging that CST plays a role in tissue homeostasis by regulating immune cell infiltration and macrophage differentiation. These findings warrant studying the effects of CST in humans and make it an interesting therapeutic target for treatment and/or diagnosis of various metabolic and immune diseases.

  • Catestatin: A Master Regulator of Cardiovascular Functions.
    Current medicinal chemistry, 2018
    Co-Authors: Sushil K. Mahata, Malapaka Kiranmayi, Nitish R. Mahapatra
    Abstract:

    Background Cardiovascular disease (CVD), the most common cause of death globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor to morbidity and mortality from CVD. Methods and results The plasma concentration of chromogranin A (CgA) is elevated in patients with CVD as well as patients with established human essential hypertension and heart failure (HF). In contrast, the plasma level of the CgA-derived peptide Catestatin (CST) is diminished in human essential hypertension. Low conversion of CgA-to-CST has been associated with increased mortality in patients hospitalized with acute HF. Consistent with human findings, the lack of CST in CgA knockout (Chga-KO) mice eventuates in the development of hypertension and supplementation of CST to Chga-KO mice restores blood pressure, implicating CST as a key player in regulating hypertension. In the peripheral system, CST decreases blood pressure by stimulating histamine release, inhibiting catecholamine secretion, or causing vasodilation. Centrally, CST improves baroreflex sensitivity (BRS) and heart rate variability (HRV) by exciting GABAergic neurons in the caudal ventrolateral medulla (CVLM) and pyramidal neurons of the central amygdala; CST also decreases BRS by exciting glutamatergic rostral ventrolateral medulla (RVLM) neurons. In addition, CST provides cardioprotection by inhibiting inotropy and lusitropy; activating mitochondrial KATP channels, and stimulating reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways and consequent inhibition of mitochondrial permeability transition pore (mPTP). CST modulates cardiomyocyte Ca2+ levels by direct inhibition of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) activity and consequent reduction in phosphorylation of phospholamban and ryanodine receptor 2, thereby providing support for a direct functional role of CST in the failing myocardium. Conclusion These multitude of effects establish CST as a master regulator of cardiovascular functions.

  • Catestatin increases the expression of anti-apoptotic and pro-angiogenetic factors in the post-ischemic hypertrophied heart of SHR.
    PloS one, 2014
    Co-Authors: Claudia Penna, Sushil K. Mahata, Bruno Tota, Teresa Pasqua, Daniela Amelio, Maria-giulia Perrelli, Carmelina Angotti, Francesca Tullio, Pasquale Pagliaro, Maria Carmela Cerra
    Abstract:

    Background In the presence of comorbidities the effectiveness of many cardioprotective strategies is blunted. The goal of this study was to assess in a hypertensive rat model if the early reperfusion with anti-hypertensive and pro-angiogenic Chromogranin A-derived peptide, Catestatin (CST:hCgA352–372; CST-Post), protects the heart via Reperfusion-Injury-Salvage-Kinases (RISK)-pathway activation, limiting infarct-size and apoptosis, and promoting angiogenetic factors (e.g., hypoxia inducible factor, HIF-1α, and endothelial nitric oxide synthase, eNOS, expression).

  • Obligatory role for endothelial heparan sulphate proteoglycans and caveolae internalization in Catestatin-dependent eNOS activation.
    BioMed research international, 2014
    Co-Authors: Sara Fornero, Sushil K. Mahata, Eleonora Bassino, Roberta Ramella, Clara Gallina, Bruno Tota, Renzo Levi, Giuseppe Alloatti, Maria Pia Gallo
    Abstract:

    The chromogranin-A peptide Catestatin modulates a wide range of processes, such as cardiovascular functions, innate immunity, inflammation, and metabolism. We recently found that the cardiac antiadrenergic action of Catestatin requires a PI3K-dependent NO release from endothelial cells, although the receptor involved is yet to be identified. In the present work, based on the cationic properties of Catestatin, we tested the hypothesis of its interaction with membrane heparan sulphate proteoglycans, resulting in the activation of a caveolae-dependent endocytosis. Experiments were performed on bovine aortic endothelial cells. Endocytotic vesicles trafficking was quantified by confocal microscopy using a water-soluble membrane dye; Catestatin colocalization with heparan sulphate proteoglycans and caveolin 1 internalization were studied by fluorimetric measurements in live cells. Modulation of the Catestatin-dependent eNOS activation was assessed by immunofluorescence and immunoblot analysis. Our results demonstrate that Catestatin (5 nM) colocalizes with heparan sulphate proteoglycans and induces a remarkable increase in the caveolae-dependent endocytosis and caveolin 1 internalization, which were significantly reduced by both heparinase and wortmannin. Moreover, Catestatin was unable to induce Ser1179 eNOS phosphorylation after pretreatments with heparinase and methyl-β-cyclodextrin. Taken together, these results highlight the obligatory role for proteoglycans and caveolae internalization in the Catestatin-dependent eNOS activation in endothelial cells.

Daniel T. O'connor - One of the best experts on this subject based on the ideXlab platform.

  • Novel roles of chromogranin A and its peptide, Catestatin, in cardioprotection (652.3)
    The FASEB Journal, 2014
    Co-Authors: Jan M. Schilling, Daniel T. O'connor, Ennio Avolio, Alice E. Zemljic-harpf, John P. Headrick, Heidi N. Fridolfsson, Adam Kassan, Gautam Bandyopadhyay, Jawed A. Siddiqui, David M. Roth
    Abstract:

    Chromogranin A (Chga) is abundant in (neuro) endocrine cells, and its derived peptide Catestatin (CST) acts as an antihypertensive, cardioprotective, pro-angiogenic, and insulin-sensitizing peptide...

  • Development of a pharmacophore model for the catecholamine release-inhibitory peptide Catestatin: virtual screening and functional testing identify novel small molecule therapeutics of hypertension.
    Bioorganic & medicinal chemistry, 2013
    Co-Authors: I Tsigelny, Sushil K. Mahata, Nilima Biswas, Valentina L. Kouznetsova, Daniel T. O'connor
    Abstract:

    The endogenous catecholamine release-inhibitory peptide Catestatin (CST) regulates events leading to hypertension and cardiovascular disease. Earlier we studied the structure of CST by NMR, molecular modeling, and amino acid scanning mutagenesis. That structure has now been exploited for elucidation of interface pharmacophores that mediate binding of CST to its target, with consequent secretory inhibition. Designed pharmacophore models allowed screening of 3D structural domains. Selected compounds were tested on both cultured catecholaminergic cells and an in vivo model of hypertension; in each case, the candidates showed substantial mimicry of native CST actions, with preserved or enhanced potency and specificity. The approach and compounds have thus enabled rational design of novel drug candidates for treatment of hypertension or autonomic dysfunction.

  • Reprint of: Catestatin: a multifunctional peptide from chromogranin A.
    Regulatory peptides, 2010
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Maple M. Fung, Daniel T. O'connor
    Abstract:

    Abstract In 1997, we identified a novel peptide, Catestatin (CST: bovine chromogranin A [CHGA]344–364: RSMRLSFRARGYGFRGPGLQL; human CHGA352–372: SSMKLSFRARGYGFRGPGPQL), which is a potent inhibitor of nicotinic-cholinergic-stimulated catecholamine secretion. CST shows characteristic inhibitory effects on nicotinic cationic (Na+, Ca2+) signal transduction, which are specific to the neuronal nicotinic receptor. Utilizing systematic polymorphism discovery at the human CHGA locus we discovered three human variants of CST: G364S, P370L, and R374Q that showed differential potencies towards the inhibition of catecholamine secretion. In humans, CHGA is elevated and its processing to CST is diminished in hypertension. Diminished CST is observed not only in hypertensive individuals but also in the early-normotensive offspring of patients with hypertension, suggesting that an early deficiency of CST might play a pathogenic role in the subsequent development of the disease. Consistent with human findings, prevention of endogenous CST expression by targeted ablation (knockout) of the mouse Chga locus (Chga-KO) resulted in severe hypertension that can be “rescued” specifically by replacement of the CST peptide. CST acts directly on the heart to inhibit the inotropic and lusitropic properties of the rodent heart and also acts as a potent vasodilator in rats and humans. While the G364S CST variant caused profound changes in human autonomic activity and seemed to reduce the risk of developing hypertension, CST replacement rescued Chga-KO mice from dampened baroreflex sensitivity. In addition, CST has been shown to induce chemotaxis and acts as an antimicrobial as well as an antimalarial peptide. The present review summarizes these multiple actions of CST.

  • Human Catestatin peptides differentially regulate infarct size in the ischemic-reperfused rat heart.
    Regulatory peptides, 2010
    Co-Authors: Bhawanjit K. Brar, Sushil K. Mahata, Daniel T. O'connor, Karen B Helle, Kuixing Zhang, Erik Helgeland, Anne K. Jonassen
    Abstract:

    Abstract In acute myocardial infarction increased plasma levels of chromogranin A are correlated with decreased survival. At the human chromogranin A gene locus there are two naturally occurring amino acid substitution variants within the Catestatin region, i.e. Gly364Ser and Pro370Leu, displaying differential potencies towards inhibition of nicotinic cholinergic agonist-evoked catecholamine secretion from sympathochromaffin cells and different degrees of processing from the prohormone. Here, we examine whether two of the variants and the wild type Catestatin may affect the development of infarct size during ischemic reperfusion in the Langendorff rat heart model. The hearts were subjected to regional ischemia followed by reperfusion in the presence or absence of synthetic variants of human Catestatin. Compared to the Gly364Ser variant both the wild type and Pro370Leu variants increased infarct size while decreasing the cardiac levels of phosphorylated Akt and two of its downstream targets, FoxO1 and BAD. In conclusion, these findings suggest that, in contrast to the Gly364Ser variant, wild type Catestatin and the Pro370Leu variant (allele frequency ~ 0.3%) increased myocardial infarct size via a mechanism involving dephosphorylation of Akt and the two downstream targets during ischemic reperfusion in the isolated rat heart.

  • Catestatin: a multifunctional peptide from chromogranin A.
    Regulatory peptides, 2010
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Maple M. Fung, Daniel T. O'connor
    Abstract:

    In 1997, we identified a novel peptide, Catestatin (CST: bovine chromogranin A [CHGA](344-364): RSMRLSFRARGYGFRGPGLQL; human CHGA(352-372): SSMKLSFRARGYGFRGPGPQL), which is a potent inhibitor of nicotinic-cholinergic-stimulated catecholamine secretion. CST shows characteristic inhibitory effects on nicotinic cationic (Na(+), Ca(2+)) signal transduction, which are specific to the neuronal nicotinic receptor. Utilizing systematic polymorphism discovery at the human CHGA locus we discovered three human variants of CST: G(364)S, P(370)L, and R(374)Q that showed differential potencies towards the inhibition of catecholamine secretion. In humans, CHGA is elevated and its processing to CST is diminished in hypertension. Diminished CST is observed not only in hypertensive individuals but also in the early-normotensive offspring of patients with hypertension, suggesting that an early deficiency of CST might play a pathogenic role in the subsequent development of the disease. Consistent with human findings, prevention of endogenous CST expression by targeted ablation (knockout) of the mouse Chga locus (Chga-KO) resulted in severe hypertension that can be "rescued" specifically by replacement of the CST peptide. CST acts directly on the heart to inhibit the inotropic and lusitropic properties of the rodent heart and also acts as a potent vasodilator in rats and humans. While the G(364)S CST variant caused profound changes in human autonomic activity and seemed to reduce the risk of developing hypertension, CST replacement rescued Chga-KO mice from dampened baroreflex sensitivity. In addition, CST has been shown to induce chemotaxis and acts as an antimicrobial as well as an antimalarial peptide. The present review summarizes these multiple actions of CST.

Manjula Mahata - One of the best experts on this subject based on the ideXlab platform.

  • Reprint of: Catestatin: a multifunctional peptide from chromogranin A.
    Regulatory peptides, 2010
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Maple M. Fung, Daniel T. O'connor
    Abstract:

    Abstract In 1997, we identified a novel peptide, Catestatin (CST: bovine chromogranin A [CHGA]344–364: RSMRLSFRARGYGFRGPGLQL; human CHGA352–372: SSMKLSFRARGYGFRGPGPQL), which is a potent inhibitor of nicotinic-cholinergic-stimulated catecholamine secretion. CST shows characteristic inhibitory effects on nicotinic cationic (Na+, Ca2+) signal transduction, which are specific to the neuronal nicotinic receptor. Utilizing systematic polymorphism discovery at the human CHGA locus we discovered three human variants of CST: G364S, P370L, and R374Q that showed differential potencies towards the inhibition of catecholamine secretion. In humans, CHGA is elevated and its processing to CST is diminished in hypertension. Diminished CST is observed not only in hypertensive individuals but also in the early-normotensive offspring of patients with hypertension, suggesting that an early deficiency of CST might play a pathogenic role in the subsequent development of the disease. Consistent with human findings, prevention of endogenous CST expression by targeted ablation (knockout) of the mouse Chga locus (Chga-KO) resulted in severe hypertension that can be “rescued” specifically by replacement of the CST peptide. CST acts directly on the heart to inhibit the inotropic and lusitropic properties of the rodent heart and also acts as a potent vasodilator in rats and humans. While the G364S CST variant caused profound changes in human autonomic activity and seemed to reduce the risk of developing hypertension, CST replacement rescued Chga-KO mice from dampened baroreflex sensitivity. In addition, CST has been shown to induce chemotaxis and acts as an antimicrobial as well as an antimalarial peptide. The present review summarizes these multiple actions of CST.

  • Catestatin: a multifunctional peptide from chromogranin A.
    Regulatory peptides, 2010
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Maple M. Fung, Daniel T. O'connor
    Abstract:

    In 1997, we identified a novel peptide, Catestatin (CST: bovine chromogranin A [CHGA](344-364): RSMRLSFRARGYGFRGPGLQL; human CHGA(352-372): SSMKLSFRARGYGFRGPGPQL), which is a potent inhibitor of nicotinic-cholinergic-stimulated catecholamine secretion. CST shows characteristic inhibitory effects on nicotinic cationic (Na(+), Ca(2+)) signal transduction, which are specific to the neuronal nicotinic receptor. Utilizing systematic polymorphism discovery at the human CHGA locus we discovered three human variants of CST: G(364)S, P(370)L, and R(374)Q that showed differential potencies towards the inhibition of catecholamine secretion. In humans, CHGA is elevated and its processing to CST is diminished in hypertension. Diminished CST is observed not only in hypertensive individuals but also in the early-normotensive offspring of patients with hypertension, suggesting that an early deficiency of CST might play a pathogenic role in the subsequent development of the disease. Consistent with human findings, prevention of endogenous CST expression by targeted ablation (knockout) of the mouse Chga locus (Chga-KO) resulted in severe hypertension that can be "rescued" specifically by replacement of the CST peptide. CST acts directly on the heart to inhibit the inotropic and lusitropic properties of the rodent heart and also acts as a potent vasodilator in rats and humans. While the G(364)S CST variant caused profound changes in human autonomic activity and seemed to reduce the risk of developing hypertension, CST replacement rescued Chga-KO mice from dampened baroreflex sensitivity. In addition, CST has been shown to induce chemotaxis and acts as an antimicrobial as well as an antimalarial peptide. The present review summarizes these multiple actions of CST.

  • Proteolytic cleavage of human chromogranin a containing naturally occurring Catestatin variants: differential processing at Catestatin region by plasmin.
    Endocrinology, 2007
    Co-Authors: Nilima Biswas, Manjula Mahata, Daniel T. O'connor, Sucheta M. Vaingankar, L Taupenot, Jiaur R. Gayen, Madhusudan Das, Justin W. Torpey, Sushil K. Mahata
    Abstract:

    The plasma level of chromogranin A (CgA) is elevated in genetic hypertension. Conversely, the plasma level of the CgA peptide Catestatin is diminished in individuals with established hypertension and those with a genetic risk of this disease. Resequencing of the human CHGA gene identified three naturally occurring variants of Catestatin (Gly364Ser, Pro370Leu, and Arg374Gln) that exhibit different potencies in inhibiting catecholamine secretion. Here, we have examined whether there is any differential processing of the three CHGA variants to Catestatin by the endoproteolytic enzyme plasmin. Plasmin digestion of the purified CgA proteins generated a stable biologically active 14-amino acid peptide (human CgA(360-373)) from the wild-type, Gly364Ser, and Arg374Gln proteins despite the disruption of the dibasic site (Arg(373)Arg(374)) in the Arg374Gln variant. Unexpectedly, the action of plasmin in generating the Catestatin peptide from the Pro370Leu protein was less efficient. The efficiency of cleavage at the dibasic Arg(373) downward arrowArg(374) site in synthetic human CgA(360-380) was 3- to 4-fold less in Pro370Leu CgA, compared with the wild type. Circular dichroism of the synthetic CgA(352-372) suggested a difference in the amount of alpha-helix and beta-sheet between the wild-type and Pro370Leu CgA peptides. Because the Pro(370) residue is in the P4 position, the local secondary structure in the vicinity of the cleavage site may enforce the specificity or accessibility to plasmin. The less efficient proteolytic processing of the Pro370Leu protein by plasmin, coupled with the strong association of this variant with ethnicity, suggests that the Pro370Leu CHGA gene variant may contribute to the differential prevalence of cardiovascular disease across ethnic groups.

  • catecholamine release inhibitory peptide Catestatin chromogranin a352 372 naturally occurring amino acid variant gly364ser causes profound changes in human autonomic activity and alters risk for hypertension
    Circulation, 2007
    Co-Authors: Fangwen Rao, Manjula Mahata, Sucheta M. Vaingankar, Rany M. Salem, Brian P. Kennedy, Jiaur R. Gayen, Madhusudan Das, Brinda K. Rana, Gen Wen, Mats Stridsberg
    Abstract:

    BACKGROUND - Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment Catestatin. We identified a natural nonsynonymous variant of Catestatin, Gly364Ser, that alters human autonomic function and blood pressure. METHODS AND RESULTS - Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its Catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by ≈47%) and downward deflections (by ≈44%), increased cardiac parasympathetic index (by ≈2.4-fold), and decreased cardiac sympathetic index (by ≈26%). Renal norepinephrine excretion was diminished by ≈26% and epinephrine excretion by ≈34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to ≈70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by ≈5 to 6 mm Hg, and the polymorphism accounted for ≈1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. CONCLUSIONS - The Catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for Catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

  • Catecholamine Release–Inhibitory Peptide Catestatin (Chromogranin A352–372) Naturally Occurring Amino Acid Variant Gly364Ser Causes Profound Changes in Human Autonomic Activity and Alters Risk for Hypertension
    Circulation, 2007
    Co-Authors: Fangwen Rao, Manjula Mahata, Sucheta M. Vaingankar, Rany M. Salem, Brian P. Kennedy, Wen, Jiaur R. Gayen, Madhusudan Das, Brinda K. Rana, Mats Stridsberg
    Abstract:

    BACKGROUND - Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment Catestatin. We identified a natural nonsynonymous variant of Catestatin, Gly364Ser, that alters human autonomic function and blood pressure. METHODS AND RESULTS - Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its Catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by ≈47%) and downward deflections (by ≈44%), increased cardiac parasympathetic index (by ≈2.4-fold), and decreased cardiac sympathetic index (by ≈26%). Renal norepinephrine excretion was diminished by ≈26% and epinephrine excretion by ≈34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to ≈70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by ≈5 to 6 mm Hg, and the polymorphism accounted for ≈1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. CONCLUSIONS - The Catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for Catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

Daniel T Oconnor - One of the best experts on this subject based on the ideXlab platform.

  • Catestatin the catecholamine release inhibitory peptide fragment of chromogranin a naturally occurring human variants displaying different potencies for multiple nicotinic cholinergic responses in chromaffin cells
    Clinical Pharmacology & Therapeutics, 2005
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Nitish R. Mahapatra, Gen Wen, William B. Wong, Bruce A. Hamilton, Daniel T Oconnor
    Abstract:

    Resequencing of the human chromogranin A gene identified three human variants of Catestatin: Gly364Ser, Pro370Leu, and Arg374Gln. Naturally occurring variants were tested for ability to inhibit four nicotinic processes. The rank order of potency for inhibition of catecholamine secretion was Pro370Leu> wild type> Gly364Ser> Arg374Gln. Decrease in potency was paralleled by decline in Hill slope, suggesting that negative cooperativity at ascending dose might underlie loss of potency. Each variant acted as a nicotinic antagonist. Potency to inhibit secretion paralleled inhibition of agonist-triggered 22Na+ uptake (r=0.986 and blockade of secretion was non-competitive with agonist. Variants also inhibited desensitization of secretion after prior agonist exposure, and stimulation of secretory protein biosynthesis by agonist. Rank order of variant inhibitory potency for all four nicotinic processes was identical (Pro370Leu > wild type > Gly364Ser > Arg374Gln), suggesting mediation by similar combinations of receptor alpha/beta subunits, and that crucial Catestatin residues are likely to be identical across the four processes. When Catestatin variants were mixed in likely heterozygotic (1:1 molar ratio) combinations, the inhibitory curve was left-shifted onto that of the more potent variant in the combination, suggesting not only phenotypic dominance. The results from four nicotinic processes have quantitative implications for inter-individual variations in human nicotinic signaling. Clinical Pharmacology & Therapeutics (2005) 77, P6–P6; doi: 10.1016/j.clpt.2004.11.027

  • catecholamine secretory vesicle stimulus transcription coupling in vivo demonstration by a novel transgenic promoter photoprotein reporter and inhibition of secretion and transcription by the chromogranin a fragment Catestatin
    Journal of Biological Chemistry, 2003
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Michael G. Ziegler, Brian P. Kennedy, Nitish R. Mahapatra, Timothy C. Wang, Daniel T Oconnor
    Abstract:

    Stimulation of chromaffin cell secretion in vitro triggers not only secretion but also resynthesis of just released catecholamines and chromogranin A, the precursor of the catecholamine release-inhibitory, nicotinic cholinergic antagonist peptide Catestatin. Does stimulus-transcription coupling occur in vivo? And does Catestatin antagonize secretion and transcription in vivo? To answer these questions, we employed a novel mouse strain harboring a chromogranin A promoter/firefly luciferase reporter transgene. Tissue-specific expression of the reporter was established by both luminescence and reverse transcription-PCR. Secretion and transcription in vivo were triggered by either direct nicotinic stimulation or vesicular transmitter depletion. Nicotinic blockade in vivo was attempted with either the classical antagonist chlorisondamine or the novel antagonist Catestatin. Luciferase reporter expression was exquisitely sensitive over a large dynamic range, was specific for the transgenic animals, and paralleled typical neuroendocrine distribution of endogenous chromogranin A. Adrenal ontogeny revealed a rise of embryonic transgene expression until embryonal day 18, with an abrupt postnatal decline. Direct nicotinic stimulation of chromaffin cells caused catecholamine release and transgene transcription, each of which was nearly completely blocked by chlorisondamine. Similar adrenal results were obtained during vesicular catecholamine depletion. Both secretion and transcription were substantially blocked in the adrenal gland by Catestatin. In brain and sympathetic nerve, stimulation of transcription was more modest, and reserpine responses were only incompletely blocked by chlorisondamine or Catestatin, perhaps because of limited blood-brain barrier penetration by these cationic antagonists. Thus, nicotinic cholinergic stimulus-transcription coupling occurs in vivo and can be provoked either directly or indirectly (by vesicular transmitter depletion). Such coupling triggers the biosynthesis of chromogranin A, the precursor of Catestatin. Catestatin itself blocks stimulation of both secretion and transcription in vivo. Thus, chromogranin A and its Catestatin fragment may lie at the nexus of nicotinic cholinergic signaling in vivo.

  • primary structure and function of the catecholamine release inhibitory peptide Catestatin chromogranin a344 364 identification of amino acid residues crucial for activity
    Molecular Endocrinology, 2000
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Arun R. Wakade, Daniel T Oconnor
    Abstract:

    The novel chromogranin A fragment Catestatin (bovine chromogranin A344−364; RSMRLSFRARGYGFRGPGLQL) is a potent inhibitor of catecholamine release (IC50, ∼0.2–0.3μ m) by acting as a nicotinic cholinergic antagonist. To define the minimal active region within Catestatin, we tested the potencies of synthetic serial three-residue deletion (amino-terminal, carboxyl-terminal, or bidirectional) fragments to inhibit nicotine-stimulated catecholamine secretion from PC12 pheochromocytoma cells. The results revealed that a completely active core sequence of Catestatin was constituted by chromogranin A344−358. Nicotinic cationic signal transduction was affected by Catestatin fragments in a manner similar to that for secretion (confirming the functional importance of the amino-terminus). To identify crucial residues within the active core, we tested serial single amino acid truncations or single residue substitutions by alanine on nicotine-induced catecholamine secretion and desensitization. Nicotinic inhibition by th...

  • desensitization of catecholamine release the novel catecholamine release inhibitory peptide Catestatin chromogranin a344 364 acts at the receptor to prevent nicotinic cholinergic tolerance
    Journal of Biological Chemistry, 1999
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Robert J Parmer, Daniel T Oconnor
    Abstract:

    Nicotinic cholinergic receptors undergo desensitization upon repeated or prolonged exposure to agonist. We investigated the effects of a novel chromogranin A catecholamine release-inhibitory fragment, Catestatin (chromogranin A344-364), on agonist-induced desensitization of catecholamine release from pheochromocytoma cells. In a dose-dependent fashion, the nicotinic antagonist Catestatin blocked agonist desensitization of both catecholamine release (IC50 approximately 0.24 microM) and 22Na+ uptake (IC50 approximately 0.31 microM), the initial step in nicotinic cationic signal transduction; both secretion inhibition and blockade of desensitization were noncompetitive with agonist. Desensitizing effects of the nicotinic agonists nicotine and epibatidine were blocked. This antagonist action was specific to desensitization by nicotinic agonists, since Catestatin did not block desensitization of catecholamine release induced by agents which bypass the nicotinic receptor. Hill plots with slopes near unity suggested noncooperativity for Catestatin effects on both nicotinic responses (secretory antagonism and blockade of desensitization). Human, bovine, and rat Catestatins (as well as substance P) had similar potencies. IC50 values for secretion inhibition and blockade of desensitization paralleled each other (r = 0.76, n = 10 antagonists, p = 0.01) for several noncompetitive nicotinic antagonists. Peptide nicotinic antagonists (Catestatins, substance P) were far more potent inhibitors of both secretion (p = 0.019) and desensitization (p = 0.005) than nonpeptide antagonists (trimethaphan, hexamethonium, procaine, phencyclidine, cocaine, or clonidine), and the peptides displayed enhanced selectivity to block desensitization versus secretion (p = 0.003). We conclude that Catestatin is a highly potent, dose-dependent, noncompetitive, noncooperative, specific inhibitor of nicotinic desensitization, an effect which may have implications for control of catecholamine release.

  • mechanism of action of chromogranin a on catecholamine release molecular modeling of the Catestatin region reveals a β strand loop β strand structure secured by hydrophobic interactions and predictive of activity
    Regulatory Peptides, 1998
    Co-Authors: I Tsigelny, Manjula Mahata, Robert J Parmer, Sushil K. Mahata, L Taupenot, N E Preece, Imran M. Khan, Daniel T Oconnor
    Abstract:

    Abstract A novel fragment of chromogranin A, known as `Catestatin' (bovine chromogranin A 344–364 ), inhibits catecholamine release from chromaffin cells and noradrenergic neurons by acting as a non-competitive nicotinic cholinergic antagonist, and may therefore constitute an endogenous autocrine feedback regulator of sympathoadrenal activity. To characterize how this activity depends on the peptide's structure, we searched for common 3-dimensional motifs for this primary structure or its homologs. Catestatin's primary structure bore significant (29–35.5% identity, general alignment score 44–57) sequence homology to fragment sequences within three homologs of known 3-dimensional structures, based on solved X-ray crystals: 8FAB, 1PKM, and 2IG2. Each of these sequences exists in nature as a β-strand/loop/β-strand structure, stabilized by hydrophobic interactions between the β-strands. The Catestatin structure was stable during molecular dynamics simulations. The Catestatin loop contains three Arg residues, whose electropositive side chains form the terminus of the structure, and give rise to substantial uncompensated charge asymmetry in the molecule. A hydrophobic moment plot revealed that Catestatin is the only segment of chromogranin A predicted to contain amphiphilic β-strand. Circular dichroism in the far ultraviolet showed substantial (63%) β-sheet structure, especially in a hydrophobic environment. Alanine-substitution mutants of Catestatin established a crucial role for the three central arginine residues in the loop (Arg 351 , Arg 353 , and Arg 358 ), though not for two arginine residues in the strand region toward the amino-terminus. [ 125 I]Catestatin bound to Torpedo membranes at a site other than the nicotinic agonist binding site. When the Catestatin structure was `docked' with the extracellular domain of the Torpedo nicotinic cholinergic receptor, it interacted principally with the β and δ subunits, in a relatively hydrophobic region of the cation pore extracellular orifice, and the complex of ligand and receptor largely occluded the cation pore, providing a structural basis for the non-competitive nicotinic cholinergic antagonist properties of the peptide. We conclude that a homology model of Catestatin correctly predicts actual features of the peptide, both physical and biological. The model suggests particular spatial and charge features of the peptide which may serve as starting points in the development of non-peptide mimetics of this endogenous nicotinic cholinergic antagonist.

Nitish R. Mahapatra - One of the best experts on this subject based on the ideXlab platform.

  • Catestatin: A Master Regulator of Cardiovascular Functions.
    Current medicinal chemistry, 2018
    Co-Authors: Sushil K. Mahata, Malapaka Kiranmayi, Nitish R. Mahapatra
    Abstract:

    Background Cardiovascular disease (CVD), the most common cause of death globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor to morbidity and mortality from CVD. Methods and results The plasma concentration of chromogranin A (CgA) is elevated in patients with CVD as well as patients with established human essential hypertension and heart failure (HF). In contrast, the plasma level of the CgA-derived peptide Catestatin (CST) is diminished in human essential hypertension. Low conversion of CgA-to-CST has been associated with increased mortality in patients hospitalized with acute HF. Consistent with human findings, the lack of CST in CgA knockout (Chga-KO) mice eventuates in the development of hypertension and supplementation of CST to Chga-KO mice restores blood pressure, implicating CST as a key player in regulating hypertension. In the peripheral system, CST decreases blood pressure by stimulating histamine release, inhibiting catecholamine secretion, or causing vasodilation. Centrally, CST improves baroreflex sensitivity (BRS) and heart rate variability (HRV) by exciting GABAergic neurons in the caudal ventrolateral medulla (CVLM) and pyramidal neurons of the central amygdala; CST also decreases BRS by exciting glutamatergic rostral ventrolateral medulla (RVLM) neurons. In addition, CST provides cardioprotection by inhibiting inotropy and lusitropy; activating mitochondrial KATP channels, and stimulating reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways and consequent inhibition of mitochondrial permeability transition pore (mPTP). CST modulates cardiomyocyte Ca2+ levels by direct inhibition of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) activity and consequent reduction in phosphorylation of phospholamban and ryanodine receptor 2, thereby providing support for a direct functional role of CST in the failing myocardium. Conclusion These multitude of effects establish CST as a master regulator of cardiovascular functions.

  • Chromogranin A: a novel susceptibility gene for essential hypertension
    Cellular and Molecular Life Sciences, 2010
    Co-Authors: Bhavani S. Sahu, Parshuram J. Sonawane, Nitish R. Mahapatra
    Abstract:

    Chromogranin A (CHGA) is ubiquitously expressed in secretory cells of the endocrine, neuroendocrine, and neuronal tissues. Although this protein has long been known as a marker for neuroendocrine tumors, its role in cardiovascular disease states including essential hypertension (EH) has only recently been recognized. It acts as a prohormone giving rise to bioactive peptides such as vasostatin-I (human CHGA_1–76) and Catestatin (human CHGA_352–372) that exhibit several cardiovascular regulatory functions. CHGA is over-expressed but Catestatin is diminished in EH. Moreover, genetic variants in the promoter, Catestatin, and 3′-untranslated regions of the human CHGA gene alter autonomic activity and blood pressure. Consistent with these findings, targeted ablation of this gene causes severe arterial hypertension and ventricular hypertrophy in mice. Transgenic expression of the human CHGA gene or exogenous administration of Catestatin restores blood pressure in these mice. Thus, the accumulated evidence establishes CHGA as a novel susceptibility gene for EH.

  • Catestatin is a novel endogenous peptide that regulates cardiac function and blood pressure.
    Cardiovascular research, 2008
    Co-Authors: Nitish R. Mahapatra
    Abstract:

    Catestatin is a 21-amino acid residue, cationic and hydrophobic peptide that is formed endogenously by proteolytic cleavage of its precursor chromogranin A, a major protein co-stored and co-released with catecholamines from the storage vesicles in adrenal chromaffin cells and adrenergic neurons. This peptide exhibits potent catecholamine release-inhibitory activity by acting on the neuronal nicotinic acetylcholine receptor. It also stimulates histamine release from mast cells via heterotrimeric G-proteins in a receptor-independent manner. Plasma levels of Catestatin are diminished not only in hypertensive patients but also in their still-normotensive offspring, indicating its role in the pathogenesis of hypertension. Consistently, exogenous Catestatin rescues hypertension in chromogranin A knockout mice and diminishes blood pressure responses to activation of sympathetic outflow in rats. These hypotensive actions of Catestatin may be caused directly by autocrine inhibition of catecholamine release from the sympathoadrenal system and indirectly by paracrine stimulation of the potent vasodilator histamine release from mast cells. Recently, three human variants of Catestatin displaying differential potencies for inhibition of catecholamine secretion have been identified. One of these variants (Gly364Ser) causes increased baroreceptor sensitivity, increased cardiac parasympathetic activity, and decreased cardiac sympathetic activity, and it seems to alter the risk for hypertension. These cardiovascular effects may have resulted by action of this peptide in the baroreceptor centre of the nucleus tractus solitarius. Thus, accumulating evidence documents the endogenous peptide Catestatin as a novel regulator of cardiac function and blood pressure.

  • The chromogranin A fragment Catestatin: specificity, potency and mechanism to inhibit exocytotic secretion of multiple catecholamine storage vesicle co-transmitters.
    Journal of hypertension, 2006
    Co-Authors: Nitish R. Mahapatra, Manjula Mahata, Sushil K. Mahata, Daniel T. O'connor
    Abstract:

    Background Secretory granules of chromaffin cells and neurons co-store and release, by exocytosis, the acidic soluble protein chromogranin A (human, CHGA; rodent, Chga) along with catecholamines, neuropeptides and adenosine triphosphate (ATP). CHGA serves as a pro-protein and upon proteolytic cleavage it generates active peptides, including Catestatin (human CHGA352-372), first discovered in adrenal medullary chromaffin granules. Studies in our laboratory demonstrated that Catestatin acts at the nicotinic acetylcholine receptor to inhibit catecholamine secretion. However, the specificity of Catestatin to exert nicotinic-cholinergic antagonism among its co-transmitters is not clearly known, nor is the potential effect of Catestatin on multiple vesicle co-transmitters understood. Aim Here we probed the specificity of Catestatin's actions among its co-transmitters: catecholamines, ATP, and neuropeptide Y (NPY). Methods We studied the effects of each transmitter on exocytotic secretion of its co-transmitters from PC12 chromaffin cells, stimulating secretion by triggering physiological pathways at multiple sites. Results We observed that, among chromaffin granule co-transmitters, only Catestatin and NPY inhibited catecholamine release induced by nicotinic-cholinergic stimulation; Catestatin was more than tenfold more potent than NPY in this setting. We also stimulated norepinephrine secretion by other chromaffin cell agonists: Catestatin blocked norepinephrine release induced by nicotine, but not by other agents (such as membrane depolarization) acting at later stages in the secretory pathway, nor by agents acting on other receptor classes. By contrast, NPY acted less specifically, blocking norepinephrine release triggered by either nicotine or membrane depolarization. Catestatin inhibited nicotinic-cholinergic co-release of all classes of chromaffin granule co-transmitters: catecholamines, chromogranins, neuropeptides, and ATP. Naturally occurring variants of human Catestatin (Gly364Ser and Pro370Leu) exhibited parallel changes in potency to inhibit secretion of catecholamines and ATP. Conclusion We conclude that, among the chromaffin granule co-transmitters, Catestatin acts as the most specific and potent inhibitor of physiological pathway (nicotinic-cholinergic) stimulated secretion. Furthermore, Catestatin generally inhibits nicotinically triggered exocytotic release of multiple co-transmitters from chromaffin granules. The results have physiological and pharmacological implications for co-transmission in the sympathochromaffin system.

  • Catestatin the catecholamine release inhibitory peptide fragment of chromogranin a naturally occurring human variants displaying different potencies for multiple nicotinic cholinergic responses in chromaffin cells
    Clinical Pharmacology & Therapeutics, 2005
    Co-Authors: Sushil K. Mahata, Manjula Mahata, Nitish R. Mahapatra, Gen Wen, William B. Wong, Bruce A. Hamilton, Daniel T Oconnor
    Abstract:

    Resequencing of the human chromogranin A gene identified three human variants of Catestatin: Gly364Ser, Pro370Leu, and Arg374Gln. Naturally occurring variants were tested for ability to inhibit four nicotinic processes. The rank order of potency for inhibition of catecholamine secretion was Pro370Leu> wild type> Gly364Ser> Arg374Gln. Decrease in potency was paralleled by decline in Hill slope, suggesting that negative cooperativity at ascending dose might underlie loss of potency. Each variant acted as a nicotinic antagonist. Potency to inhibit secretion paralleled inhibition of agonist-triggered 22Na+ uptake (r=0.986 and blockade of secretion was non-competitive with agonist. Variants also inhibited desensitization of secretion after prior agonist exposure, and stimulation of secretory protein biosynthesis by agonist. Rank order of variant inhibitory potency for all four nicotinic processes was identical (Pro370Leu > wild type > Gly364Ser > Arg374Gln), suggesting mediation by similar combinations of receptor alpha/beta subunits, and that crucial Catestatin residues are likely to be identical across the four processes. When Catestatin variants were mixed in likely heterozygotic (1:1 molar ratio) combinations, the inhibitory curve was left-shifted onto that of the more potent variant in the combination, suggesting not only phenotypic dominance. The results from four nicotinic processes have quantitative implications for inter-individual variations in human nicotinic signaling. Clinical Pharmacology & Therapeutics (2005) 77, P6–P6; doi: 10.1016/j.clpt.2004.11.027