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

Bhavani S. Sahu, Jagan M. Obbineni, Giriraj Sahu, Prasanna K.R. Allu, Lakshmi Subramanian, Parshuram J. Sonawane, Pradeep K. Singh, Binu K. Sasi, Sanjib Senapati, Samir K. Maji, Amal K. Bera, Balashankar S. Gomathi, Ajit S. Mullasari, Nitish R. Mahapatra

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 resequenced 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 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.

Original languageEnglish (US)
Pages (from-to)43840-43852
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number52
DOIs
StatePublished - Dec 21 2012

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