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Molecular interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor

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Title Molecular interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor
 
Creator SAHU, BS
OBBINENI, JM
SAHU, G
SINGH, PK
SONAWANE, PJ
SASI, BK
ALLU, PKR
MAJI, SK
BERA, AK
SENAPATI, S
MAHAPATRA, NR
 
Subject Hypertension
Structure-function
nAChR
Catestatin
Human variation
CHROMOGRANIN-A FRAGMENT
NERVE GROWTH-FACTOR
CATECHOLAMINE RELEASE
ESSENTIAL-HYPERTENSION
BLOOD-PRESSURE
PC12 CELLS
PROTEIN INTERACTIONS
ENDOGENOUS PEPTIDE
PHOSPHATIDIC-ACID
MECHANISM
 
Description Catestatin (CST), a chromogranin-A-derived peptide, is a potent endogenous inhibitor of the neuronal nicotinic acetylcholine receptor (nAChR). It exerts an anti-hypertensive effect by acting as a 'physiological brake' on transmitter release into the circulation. However, the mechanism of interaction of CST with nAChR is only partially understood. To unravel molecular interactions of the wild-type human CST (CST-WT) as well as its naturally occurring variants (CST-364S and CST-370L, which have Gly -> Ser and Pro -> Leu substitutions, respectively) with the human alpha 3 beta 4 nAChR, we generated a homology-modeled human alpha 3 beta 4 nAChR structure and solution structures of CST peptides. Docking and molecular dynamics simulations showed that similar to 90% of interacting residues were within 15 N-terminal residues of CST peptides. The rank order of binding affinity of these peptides with nAChR was: CST-370L > CST-WT > CST-364S; the extent of occlusion of the receptor pore by these peptides was also in the same order. In corroboration with computational predictions, circular dichroism analysis revealed significant differences in global structures of CST peptides (e. g. the order of alpha-helical content was: CST-370L > CST-WT > CST-364S). Consistently, CST peptides blocked various stages of nAChR signal transduction, such as nicotine-or acetylcholine-evoked inward current, rise in intracellular Ca2+ and catecholamine secretion in or from neuron-differentiated PC12 cells, in the same rank order. Taken together, this study shows molecular interactions between human CST peptides and human alpha 3 beta 4 nAChR, and demonstrates that alterations in the CST secondary structure lead to the gain of potency for CST-370L and loss of potency for CST-364S. These findings have implications for understanding the nicotinic cholinergic signaling in humans.
 
Publisher COMPANY OF BIOLOGISTS LTD
 
Date 2014-10-15T10:40:47Z
2014-10-15T10:40:47Z
2012
 
Type Article
 
Identifier JOURNAL OF CELL SCIENCE, 125(9)2323-2337
http://dx.doi.org/10.1242/jcs.103176
http://dspace.library.iitb.ac.in/jspui/handle/100/14770
 
Language en