QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.002139v1 66/5/1180    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mahata, S. K. Articles by O'Connor, D. T. Search for Related Content PubMed PubMed Citation Articles by Mahata, S. K. Articles by O'Connor, D. T.

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

Department of Medicine and Center for Molecular Genetics, University of California; and VA San Diego Healthcare System, San Diego, California

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 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. Several lines of evidence indicated that each variant acted as a nicotinic antagonist: potency to inhibit secretion paralleled inhibition of agonist-triggered ²²Na⁺ uptake (r = 0.986); variants inhibited secretion with similar potency when triggered by several nicotinic agonists, though not by agents using other secretory pathways or bypassing the nicotinic receptor; and blockade of secretion was noncompetitive 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 / 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 M ratio) combinations, the inhibitory curve was left-shifted onto that of the more potent variant in the combination, suggesting phenotypic dominance. The results have quantitative implications for interindividual variations in human nicotinic signaling.

Address correspondence to: Dr. Sushil K. Mahata, University of California at San Diego and VASDHS (0838), 9500 Gilman Drive, San Diego, CA 92093-0838. E-mail: smahata{at}ucsd.edu

This article has been cited by other articles:

				D. T. O'Connor, G. Zhu, F. Rao, L. Taupenot, M. M. Fung, M. Das, S. K. Mahata, M. Mahata, L. Wang, K. Zhang, et al. Heritability and Genome-Wide Linkage in US and Australian Twins Identify Novel Genomic Regions Controlling Chromogranin A: Implications for Secretion and Blood Pressure Circulation, July 15, 2008; 118(3): 247 - 257. [Abstract] [Full Text] [PDF]

				R. Mazza, A. Gattuso, C. Mannarino, B. K. Brar, S. F. Barbieri, B. Tota, and S. K. Mahata Catestatin (chromogranin A344-364) is a novel cardiosuppressive agent: inhibition of isoproterenol and endothelin signaling in the frog heart Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H113 - H122. [Abstract] [Full Text] [PDF]

				N. R. Mahapatra Catestatin is a novel endogenous peptide that regulates cardiac function and blood pressure Cardiovasc Res, June 25, 2008; (2008) cvn155v2. [Abstract] [Full Text] [PDF]

				N. Biswas, S. M. Vaingankar, M. Mahata, M. Das, J. R. Gayen, L. Taupenot, J. W. Torpey, D. T. O'Connor, and S. K. Mahata Proteolytic Cleavage of Human Chromogranin A Containing Naturally Occurring Catestatin Variants: Differential Processing at Catestatin Region by Plasmin Endocrinology, February 1, 2008; 149(2): 749 - 757. [Abstract] [Full Text] [PDF]

				F. Rao, J. Wessel, G. Wen, L. Zhang, B. K. Rana, B. P. Kennedy, T. A. Greenwood, R. M. Salem, Y. Chen, S. Khandrika, et al. Renal Albumin Excretion: Twin Studies Identify Influences of Heredity, Environment, and Adrenergic Pathway Polymorphism Hypertension, May 1, 2007; 49(5): 1015 - 1031. [Abstract] [Full Text] [PDF]

				G. N. Hendy, T. Li, M. Girard, R. C. Feldstein, S. Mulay, R. Desjardins, R. Day, A. C. Karaplis, M. L. Tremblay, and L. Canaff Targeted Ablation of the Chromogranin A (Chga) Gene: Normal Neuroendocrine Dense-Core Secretory Granules and Increased Expression of Other Granins Mol. Endocrinol., August 1, 2006; 20(8): 1935 - 1947. [Abstract] [Full Text] [PDF]

				T. A. Greenwood, F. Rao, M. Stridsberg, N. R. Mahapatra, M. Mahata, E. O. Lillie, S. K. Mahata, L. Taupenot, N. J. Schork, and D. T. O'Connor Pleiotropic effects of novel trans-acting loci influencing human sympathochromaffin secretion Physiol Genomics, May 16, 2006; 25(3): 470 - 479. [Abstract] [Full Text] [PDF]