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First published on July 3, 2007; DOI: 10.1124/mol.107.035527

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Received for publication February 27, 2007.
Revised June 12, 2007.
Accepted for publication July 3, 2007.

Structural determinates for apolipoproteinE-derived peptide interaction with the {alpha}7 nicotinic acetylcholine receptor

Elaine Gay 1, Rachelle Bienstock 1, Patricia Lamb 1, Jerrel L. Yakel 1*

1 NIEHS/NIH

* Address correspondence to: E-mail: yakel{at}niehs.nih.gov

Abstract

Neuronal nicotinic acetylcholine receptor (nAChR) signaling has been implicated in a variety of normal CNS function as well as an array of neuropathologies. Previous studies have demonstrated both neurotoxic and neuroprotective actions of peptides derived from apolipoprotein E (apoE). Recently it was discovered that apoE-derived peptides inhibit native and recombinant {alpha}7-containing nAChRs, indicating a direct interaction between apoE peptides and nAChRs. In order to probe the structure/function interaction between {alpha}7 nAChRs and the apoE peptide, apoE141-148, experiments were conducted in Xenopus oocytes expressing wildtype and mutated nAChRs. Mutation of tryptophan (W) 55 to alanine blocks apoE peptide-induced inhibition of ACh-mediated {alpha}7 nAChR responses. Additional mutations at W55 suggest that hydrophobic interactions between the receptor and apoE141-148 are key for inhibition of {alpha}7 nAChR function. A mutated apoE peptide also demonstrated decreased inhibition at {alpha}7-W55A nAChRs as well as activity-dependent inhibition of both wildtype {alpha}7 nAChRs and {alpha}7-W55A receptors. Finally, a three-dimensional model of the {alpha}7 nAChR was developed based on the recently refined Torpedo nACh receptor. A structural model is proposed for the binding of apoE141-148 to the {alpha}7 nAChR where the peptide binds at the interface between two subunits, near the ACh binding site. Similar to the functional data, the computational docking suggests the importance of hydrophobic interactions between the {alpha}7 nAChR and the apoE peptide for inhibition of receptor function. The current data suggest a mode for apoE peptide binding that directly blocks {alpha}7 nAChR activity, and consequently may disrupt nAChR signaling.


Key words: Nicotinic cholinergic, Molecular dynamics, Structure-activity relationships and modeling, Func. analysis receptor/ion channel mutants


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 J. Physiol.Home page
E. A. Gay, R. Giniatullin, A. Skorinkin, and J. L. Yakel
Aromatic residues at position 55 of rat {alpha}7 nicotinic acetylcholine receptors are critical for maintaining rapid desensitization
J. Physiol., February 15, 2008; 586(4): 1105 - 1115.
[Abstract] [Full Text] [PDF]


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