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

Abstract

SummaryCatestatin (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 GlyRSer and ProRLeu substitutions, respectively) with the human a3b4 nAChR, we generated a homology-modeled human a3b4 nAChR structure and solution structures of CST peptides. Docking and molecular dynamics simulations showed that ,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 a-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 Ca 2+ 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 a3b4 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.

Terminally Differentiated Epithelial Cells of the Thymic Medulla and Skin Express Nicotinic Acetylcholine Receptor Subunitα3

“…The present findings suggest that its thymic production and/or release are under cholinergic control involving nAChR containing the α 3-subunit. On the other hand, catestatin is an inhibitor of α 3 β 4 nAChR [49], so that it might act in an autoinhibitory feedback in α 3-subunit-expressing terminally differentiated mTEC.…”

“Unclassical” Combination of Smell Dysfunction, Altered Abdominal Nociception and Human Hypertension Associated “Classical” Adrenal-Augmentation

“…Germane to acetylcholine receptors involvement, alpha-3 nicotinic receptor [27], regulates CGA, a protein stored and co-released with catecholamines [28]. CGA potentiated the visceromotor response to the nociceptive action of capsaicin which modulates C-fiber activity [29, 30].…”

Physical and virtual screening methods for marine toxins and drug discovery targeting nicotinic acetylcholine receptors

“…When applied to the interaction between a-conotoxins and AChBP, this new molecular modeling tool gave good results compared with experimental available data [120]. In another recent study, docking and MD simulations of an a3b4 nAChR homology model with calestatin, a known endogenous peptide inhibitor of nAChRs, showed that this peptide acts by occluding the pore in the extracellular vestibule region of the receptor [121].…”