Abstract
Neuronal nicotinic acetylcholine receptor (nAChR) signaling has been implicated in a variety of normal central nervous system (CNS) functions as well as an array of neuropathologies. Previous studies have demonstrated both neurotoxic and neuroprotective actions of peptides derived from apolipoprotein E (apoE). It has been discovered that apoE-derived peptides inhibit native and recombinant α7-containing nAChRs, indicating a direct interaction between apoE peptides and nAChRs. To probe the structure/function interaction between α7 nAChRs and the apoE peptide apoE141–148, experiments were conducted in Xenopus laevis oocytes expressing wild-type and mutated nAChRs. Mutation of Trp55 to alanine blocks apoE peptide-induced inhibition of acetylcholine (ACh)-mediated α7 nAChR responses. Additional mutations at Trp55 suggest that hydrophobic interactions between the receptor and apoE141–148 are essential for inhibition of α7 nAChR function. A mutated apoE peptide also demonstrated decreased inhibition at α7-W55A nAChRs as well as activity-dependent inhibition of both wild-type α7 nAChRs and α7-W55A receptors. Finally, a three-dimensional model of the α7 nAChR was developed based on the recently refined Torpedo marmorata nACh receptor. A structural model is proposed for the binding of apoE141–148 to the α7 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 α7 nAChR and the apoE peptide for inhibition of receptor function. The current data suggest a mode for apoE peptide binding that directly blocks α7 nAChR activity and consequently may disrupt nAChR signaling.
Footnotes
-
This research was supported by the Intramural Research Program of the National Institutes of Health.
-
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
-
doi:10.1124/mol.107.035527.
-
ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; CNS, central nervous system; ACh, acetylcholine; apoE, apolipoprotein E; MLA, methyllycaconitine; α-BgTx, α-bungarotoxin; PDB, Protein Data Bank; RMS, root-mean-square; AChBP, acetylcholine binding protein.
-
↵ The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received February 26, 2007.
- Accepted July 3, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|