Functional genetic variants of the catecholamine-release-inhibitory peptide catestatin in an Indian population: allele-specific effects on metabolic traits

• Published in: The Journal of biological chemistry 2012-12, Vol.287 (52), p.43840-43852
• Main Authors: Sahu, Bhavani S, Obbineni, Jagan M, Sahu, Giriraj, Allu, Prasanna K R, Subramanian, Lakshmi, Sonawane, Parshuram J, Singh, Pradeep K, Sasi, Binu K, Senapati, Sanjib, Maji, Samir K, Bera, Amal K, Gomathi, Balashankar S, Mullasari, Ajit S, Mahapatra, Nitish R
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Animals; Blood Glucose - metabolism; Cardiovascular Diseases - blood; Cardiovascular Diseases - genetics; Chromogranin A - chemistry; Chromogranin A - genetics; Chromogranin A - metabolism; Chromogranin A - pharmacology; Circular Dichroism; Epinephrine - metabolism; Female; Humans; India; Male; Metabolic Diseases - blood; Metabolic Diseases - genetics; Molecular Bases of Disease; Molecular Docking Simulation; Molecular Dynamics Simulation; Nicotine - pharmacology; Nicotinic Agonists - pharmacology; Norepinephrine - metabolism; PC12 Cells; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Protein Structure, Secondary; Quantitative Trait Loci; Rats; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Triglycerides - blood
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.407916

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.