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Journal article
Role of Key Aromatic Residues in the Ligand-binding Domain of alpha 7 Nicotinic Receptors in the Agonist Action of beta-Amyloid
The Journal of biological chemistry, v 286(39), pp 34373-34381
30 Sep 2011
PMID: 21828053
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Soluble beta-amyloid (A beta) resides in certain regions of the brain at or near picomolar concentration, rising in level during the prodromic stage of Alzheimer disease. Recently, we identified the homomeric alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) as one possible functional target for picomolar A beta. This study was aimed at addressing which residues in alpha 7-nAChRs potentially interact with A beta to regulate the presynaptic function of this receptor. Site-directed mutagenesis was carried out to study the key aromatic residues in the mouse alpha 7-nAChR agonist-binding pocket. Mutations of tyrosine188 resulted in a decrease in activation of presynaptic alpha 7-nAChRs by ACh and A beta but with no change in response to nicotine, indicating the critical role of Tyr-188 in presynaptic regulation by A beta. Coimmunoprecipitation additionally revealed direct binding of A beta to alpha 7-nAChRs and to the Tyr-188 mutant receptor. In contrast, mutations of Tyr-195 in alpha 7-nAChR led to decreased activation by nicotine without apparent effects on ACh- or A beta-induced responses. Agonist-induced responses of Tyr-93 mutant alpha 7-nAChRs indicated possible interactions of nicotine and A beta with its hydroxyl group, but there was no change in presynaptic responses after mutation of Trp-149. All of the mutants were shown to be expressed on the plasma membrane using cell surface labeling. Together, these results directly demonstrate an essential role for the aromatic residue Tyr-188 as a key component in the agonist binding domain for the activation of alpha 7-nAChRs by A beta
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Details
- Title
- Role of Key Aromatic Residues in the Ligand-binding Domain of alpha 7 Nicotinic Receptors in the Agonist Action of beta-Amyloid
- Creators
- Mei Tong - University of Hawaii at ManoaKomal Arora - University of Hawaii at ManoaMichael M. White - Drexel UniversityRobert A. Nichols - University of Hawaii at Manoa
- Publication Details
- The Journal of biological chemistry, v 286(39), pp 34373-34381
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 9
- Grant note
- American Health Assistance Foundation; BrightFocus Foundation G12 RR003061 / National Center for Research Resources of the National Institutes of Health via Research Centers in Minority Institutions P20RR016453 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) P20 RR016453 / Centers of Biomedical Research Excellence; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) The Hawaii Community Foundation AG21586 / National Institute on Aging; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) R01AG021586 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000295159200065
- Scopus ID
- 2-s2.0-80053215529
- Other Identifier
- 991019167918204721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology