title: Functional genetic variants of the catecholamine-release-inhibitory peptide catestatin in an Indian population: allele-specific effects on metabolic traits.
abstract: 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 Ca(2+) 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 α-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 ∼15% subjects) was strongly associated with profound reduction (up 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.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, India.
authors.forename: Bhavani S
authors.initials: BS
authors.lastname: Sahu
authors.forename: Jagan M
authors.initials: JM
authors.lastname: Obbineni
authors.forename: Giriraj
authors.initials: G
authors.lastname: Sahu
authors.forename: Prasanna K R
authors.initials: PK
authors.lastname: Allu
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Subramanian
authors.forename: Parshuram J
authors.initials: PJ
authors.lastname: Sonawane
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
authors.forename: Binu K
authors.initials: BK
authors.lastname: Sasi
authors.forename: Sanjib
authors.initials: S
authors.lastname: Senapati
authors.forename: Samir K
authors.initials: SK
authors.lastname: Maji
authors.forename: Amal K
authors.initials: AK
authors.lastname: Bera
authors.forename: Balashankar S
authors.initials: BS
authors.lastname: Gomathi
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Mullasari
authors.forename: Nitish R
authors.initials: NR
authors.lastname: Mahapatra
mesh_terms: D000328:Adult; D000483:Alleles; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics; D053379:Chromogranin A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002942:Circular Dichroism; D004837:Epinephrine / Q000378:metabolism; D005260:Female; D006801:Humans; D007194:India; D008297:Male; D008659:Metabolic Diseases / Q000097:blood / Q000235:genetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D017433:Protein Structure, Secondary; D040641:Quantitative Trait Loci; D051381:Rats; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D053379:Chromogranin A; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; D014280:Triglycerides; C109084:chromogranin A (344-364); D009538:Nicotine; D009638:Norepinephrine; D004837:Epinephrine