The Catecholamine Release-Inhibitory “Catestatin” Fragment of Chromogranin A: Naturally Occurring Human Variants with Different Potencies for Multiple Chromaffin Cell Nicotinic Cholinergic Responses

  title={The Catecholamine Release-Inhibitory “Catestatin” Fragment of Chromogranin A: Naturally Occurring Human Variants with Different Potencies for Multiple Chromaffin Cell Nicotinic Cholinergic Responses},
  author={Sushil K. Mahata and Manjula Mahata and Gen Wen and W B Wong and Nitish R. Mahapatra and Bruce A. Hamilton and Daniel T. O'Connor},
  journal={Molecular Pharmacology},
  pages={1180 - 1191}
The catestatin fragment of chromogranin A is an endogenous inhibitor of nicotinic cholinergic transmission, functioning in negative feedback control of catecholamine secretion. We explored naturally occurring polymorphisms in the amino acid sequence of catestatin. Three human variants were identified: Gly364Ser, Pro370Leu, and Arg374Gln. Variants were tested for ability to inhibit four nicotinic processes. The rank order of potency for inhibition of catecholamine secretion was Pro370Leu > wild… 

The chromogranin A fragment catestatin: specificity, potency and mechanism to inhibit exocytotic secretion of multiple catecholamine storage vesicle co-transmitters

Among the chromaffin granule co-transmitters, catestatin acts as the most specific and potent inhibitor of physiological pathway (nicotinic–cholinergic) stimulated secretion.

Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population

Interestingly, the Ser-364 allele (detected in ∼15% subjects) was strongly associated with profound reduction in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT.

The catecholamine release-inhibitory peptide catestatin (chromogranin A344-364) modulates myocardial function in fish

This is the first report in fish that CST modulates myocardial performance under basal, as well as under increased preload, conditions and counteracts the adrenergic-mediated positive inotropism, which strikingly supports the evolutionary significance and establishes the cardioactive role of this peptide.

Novel Peptide Isomer Strategy for Stable Inhibition of Catecholamine Release: Application to Hypertension

Novel peptide chemistry is undertaken to synthesize isomers of catestatin: normal/wild-type as well as a retro-inverso (R-I) version, with not only inversion of chirality but also reversal of sequence, which points the way toward a potential new class of drug therapeutics for an important risk trait and opens the door to broader applications of the R-I strategy in other pathways involved in cardiovascular biology.

Molecular interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor

Molecular interactions between human CST peptides and human α3β4 nAChR are shown, and it is demonstrated that alterations in the CST secondary structure lead to the gain of potency for CST-370L and loss of potencyFor CST-364S, having implications for understanding the nicotinic cholinergic signaling in humans.

Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart.

The cardiotropic actions of Cts, including the beta-adrenergic and ET-1 antagonistic effects, support a novel role of this peptide as an autocrine-paracrine modulator of cardiac function, particularly when the stressed heart becomes a preferential target of both adrenergic andET-1 stimuli.

Acetylcholine nicotinic receptor subtypes in chromaffin cells

  • M. Criado
  • Biology, Chemistry
    Pflügers Archiv - European Journal of Physiology
  • 2017
In the adrenal gland, acetylcholine released on stimulation of the sympathetic splanchnic nerve activates neuronal-type nicotinic receptors (nAChRs) in chromaffin cells and triggers catecholamine secretion, which can act as agonists, antagonists or allosteric modulators.

Proteolytic cleavage of human chromogranin a containing naturally occurring catestatin variants: differential processing at catestatin region by 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 Pro 370Leu CHGA gene variant may contribute to the differential prevalence of cardiovascular disease across ethnic groups.

Catestatin, a chromogranin A-derived peptide, is sympathoinhibitory and attenuates sympathetic barosensitivity and the chemoreflex in rat CVLM.

  • A. H. GaedeP. Pilowsky
  • Biology
    American journal of physiology. Regulatory, integrative and comparative physiology
  • 2012
The results suggest that catestatin plays an important role in central cardiorespiratory control in urethane-anesthetized, bilaterally vagotomized, artificially ventilated Sprague-Dawley rats.

Reprint of: Catestatin: A multifunctional peptide from chromogranin A





It is concluded 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.

Novel autocrine feedback control of catecholamine release. A discrete chromogranin a fragment is a noncompetitive nicotinic cholinergic antagonist.

This small domain within chromogranin A may contribute to a novel, autocrine, homeostatic (negative-feedback) mechanism controlling catecholamine release from chromaffin cells and neurons.

Primary structure and function of the catecholamine release inhibitory peptide catestatin (chromogranin A(344-364)): identification of amino acid residues crucial for activity.

It is concluded that a small, 15-amino acid core of catestatin (chromogranin A(344-364)) is sufficient to exert the peptide's typical inhibitory effects on nicotinic cholinergic-stimulated catecholamine secretion, signal transduction, and desensitization.

Chromaffin cell catecholamine secretion: bisindolylmaleimide compounds exhibit novel and potent antagonist effects at the nicotinic cholinergic receptor in pheochromocytoma cells.

It is concluded that bisindolylmaleimides I through III are some of the most potent noncompetitive neuronal nicotinic antagonists, indeed themost potent such antagonists the authors have observed in PC-12 cells.

Modulatory Mechanism of the Endogenous Peptide Catestatin on Neuronal Nicotinic Acetylcholine Receptors and Exocytosis

The results suggest that catestatin might play an autocrine regulatory role in neuroendocrine secretion through its interaction with different native nAChR subtypes; the extent of receptor blockade by the peptide could be acutely regulated by the intensity and duration of the presynaptic stimulus.

Formation of the Catecholamine Release-inhibitory Peptide Catestatin from Chromogranin A

It is concluded that catestatin is cleaved extensively in vivo, and the peptide is released by exocytosis as demonstrated by radioimmunoassay of size-fractionated chromaffin granules.

Early decline in the catecholamine release-inhibitory peptide catestatin in humans at genetic risk of hypertension.

It is concluded that catestatin is diminished early in the course of development of hypertension, even in the normotensive offspring of patients with the disease.

Vesicular monoamine transport inhibitors. Novel action at calcium channels to prevent catecholamine secretion.

It is concluded that VMAT inhibitors and L-type calcium channel antagonists exert reciprocal inhibitory actions on each other's more classic pharmacological targets, likely to occur during antihypertensive treatment in vivo.

Human chromogranin A. Purification and characterization from catecholamine storage vesicles of human pheochromocytoma.

A new probe of human sympathoadrenal function is available in chromogranin A, a 68,000 dalton monomeric protein with an unusual amino acid composition and marked dissimilarity to dopamine-beta-hydroxylase in all properties studied.

Peptidergic activation of transcription and secretion in chromaffin cells. Cis and trans signaling determinants of pituitary adenylyl cyclase-activating polypeptide (PACAP).

PACAP signals to chromogranin A transcription through the CRE in cis, and through PKA and CREB in trans, suggesting that the CRE domain is also sufficient to mediate the transcriptional response to PACAP.