Paper Citing NAMD - Abstract
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.
Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population ALLELE-SPECIFIC EFFECTS ON METABOLIC TRAITS
JOURNAL OF BIOLOGICAL CHEMISTRY, 287:43840-43852, DEC 21 2012
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.
