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

• Published in: Journal of cell science
• Main Authors: Sahu, Bhavani S., Mohan, Jagan, Sahu, Giriraj, Singh, Pradeep K., Sonawane, Parshuram J., Sasi, Binu K., Allu, Prasanna K. R., Maji, Samir K., Bera, Amal K., Senapati, Sanjib, Mahapatra, Nitish R.
• Format: Journal Article
• Language: English
• Published: 01.01.2012
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.103176

Catestatin (CST), a chromogranin A-derived peptide, is a potent endogenous inhibitor of the neuronal nicotinic acetylcholine receptor (nAChR). It exerts 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 common/wild type human CST (CST-WT) as well as its naturally-occurring variants (viz. CST-364S and CST-370L having Gly→Ser and Pro→Leu substitutions, respectively) with the human α3β4 nAChR we generated a homology-modeled human α3β4 nAChR structure and solution structures of CST peptides. Docking and molecular dynamics simulations showed that ∼90% of interacting residues were within the N-terminal 15-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 (viz. nicotine/acetylcholine-evoked inward current, intracellular-calcium rise, catecholamine secretion in/from neuron-differentiated PC12 cells) in the same rank order. Taken together, this study showed molecular interactions between human CST peptides and human α3β4 nAChR, and demonstrated that alterations in the CST secondary structure led to the gain of potency for CST-370L and loss of potency for CST-364S. These novel findings have implications for understanding the nicotinic cholinergic signaling in humans.