1. Functional Genetic Variants of the Catecholamine-Release-Inhibitory Peptide Catestatin in an Indian Population ALLELE-SPECIFIC EFFECTS ON METABOLIC TRAITS
- Author
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Sahu, B.S., Obbineni, J.M., Sahu, G., Allu, P.K.R., Subramanian, L., Sonawane, P.J., Singh, P.K., Sasi, B.K., Senapati, S., Maji, S.K., Bera, A.K., Gomathi, B.S., Mullasari, A.S., and Mahapatra, N.R.
- Subjects
Blood Glucose ,Male ,Genetic variants ,Amino acid substitution ,Potent inhibitor ,animal cell ,Receptors, Nicotinic ,Chromogranin-A Fragment ,adrenalin ,PC12 Cells ,Elevated level ,Protein Structure, Secondary ,Glucose level ,Norepinephrine ,single nucleotide polymorphism ,catecholamine release ,Nicotinic Acetylcholine-Receptor ,binding affinity ,genetic variability ,rat ,Nicotinic Agonists ,glucose ,calcium cell level ,Endogenous Peptide ,Molecular-Dynamics ,Circular Dichroism ,Indian ,CD spectroscopy ,catestatin ,Wild types ,Helical content ,Molecular Docking Simulation ,Enzyme inhibition ,priority journal ,Cardiovascular Diseases ,Blood-Pressure ,Hypertension ,Nicotinic acetylcholine receptors (nAChR) ,Amino acids ,Female ,Adrenal chromaffin cells ,Mechanism ,triacylglycerol ,Granule Biogenesis ,receptor down regulation ,Adult ,Binding affinities ,Nicotine ,Plasma triglycerides ,Epinephrine ,noradrenalin ,Quantitative Trait Loci ,India ,Intracellular Ca ,Binding energy ,Molecular dynamics ,Molecular Dynamics Simulation ,Biochemical parameters ,Metabolic Diseases ,Linkage disequilibrium ,Animals ,Humans ,controlled study ,noradrenalin blood level ,Genetic variation ,human ,Rank order ,Alleles ,Triglycerides ,Pancreastatin ,nonhuman ,Molecular dynamics simulations ,Protein ,Circular dichroism spectroscopy ,nucleotide sequence ,triacylglycerol blood level ,Peptide Fragments ,amino acid sequence ,gene linkage disequilibrium ,Rats ,adrenalin blood level ,glucose blood level ,Genes ,Chromogranin A ,metabolic syndrome X ,Peptides ,nicotinic receptor - 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 ?-helical content: CST-WT >, 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. � 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
- Published
- 2012