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Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population ALLELE-SPECIFIC EFFECTS ON METABOLIC TRAITS

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Title Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population ALLELE-SPECIFIC EFFECTS ON METABOLIC TRAITS
 
Creator SAHU, BS
OBBINENI, JM
SAHU, G
ALLU, PKR
SUBRAMANIAN, L
SONAWANE, PJ
SINGH, PK
SASI, BK
SENAPATI, S
MAJI, SK
BERA, AK
GOMATHI, BS
MULLASARI, AS
MAHAPATRA, NR
 
Subject NICOTINIC ACETYLCHOLINE-RECEPTOR
CHROMOGRANIN-A FRAGMENT
ENDOGENOUS PEPTIDE
MOLECULAR-DYNAMICS
GRANULE BIOGENESIS
BLOOD-PRESSURE
HYPERTENSION
MECHANISM
PROTEIN
PANCREASTATIN
 
Description Catestatin (CST), a chromogranin A (CHGA)-derived peptide, is a potent inhibitor of catecholamine release from adrenal chromaffin cells and postganglionic sympathetic axons. We re-sequenced the CST region of CHGA in an Indian population (n = 1010) and detected two amino acid substitution variants: G364S and G367V. Synthesized CST variant peptides (viz. CST-Ser-364 and CST-Val-367) were significantly less potent than the wild type peptide (CST-WT) to inhibit nicotine-stimulated catecholamine secretion from PC12 cells. Consistently, the rank-order of blockade of nicotinic acetylcholine receptor (nAChR)-stimulated inward current and intracellular Ca2+ rise by these peptides in PC12 cells was: CST-WT > CST-Ser-364 > CST-Val-367. Structural analysis by CD spectroscopy coupled with molecular dynamics simulations revealed the following order of alpha-helical content: CST-WT > CST-Ser-364 > CST-Val-367; docking of CST peptides onto a major human nAChR subtype and molecular dynamics simulations also predicted the above rank order for their binding affinity with nAChR and the extent of occlusion of the receptor pore, providing a mechanistic basis for differential potencies. The G364S polymorphism was in strong linkage disequilibrium with several common CHGA genetic variations. Interestingly, the Ser-364 allele (detected in similar to 15% subjects) was strongly associated with profound reduction (up to similar to 2.1-fold) in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT. Additionally, the Ser-364 allele showed strong associations with elevated levels of plasma triglyceride and glucose levels. In conclusion, a common CHGA variant in an Indian population influences several biochemical parameters relevant to cardiovascular/metabolic disorders.
 
Publisher AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
 
Date 2014-10-15T10:41:17Z
2014-10-15T10:41:17Z
2012
 
Type Article
 
Identifier JOURNAL OF BIOLOGICAL CHEMISTRY, 287(52)43840-43852
http://dx.doi.org/10.1074/jbc.M112.407916
http://dspace.library.iitb.ac.in/jspui/handle/100/14771
 
Language en