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Effects of mutations at conserved TM II residues on ligand binding and activation of mouse 5-HT 6 receptor

Zhang, Jiaping ; Shen, Chun-Pyn ; Xiao, Jing C ; Lanza, Thomas J ; Lin, Linus S ; Francis, Barbara E ; Fong, Tung M ; Chen, Richard Z

European Journal of Pharmacology, 2006, Vol.534(1), pp.77-82 [Peer Reviewed Journal]

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  • Title:
    Effects of mutations at conserved TM II residues on ligand binding and activation of mouse 5-HT 6 receptor
  • Author: Zhang, Jiaping ; Shen, Chun-Pyn ; Xiao, Jing C ; Lanza, Thomas J ; Lin, Linus S ; Francis, Barbara E ; Fong, Tung M ; Chen, Richard Z
  • Description: An aspartate residue (Asp-72) in the transmembrane helix II of mouse 5-hydroxytryptamine-6 receptor (5-HT ) is conserved among most G protein-coupled receptors. We have examined the functional significance of this residue by site-directed mutagenesis. A single Asp → Ala (D72A) mutation resulted in an 8-fold decrease in apparent affinity for 5-HT, and a 60-fold reduction in EC value of agonist-induced stimulation of adenylyl cyclase. A F69L/T70I/D72A triple mutant showed a 2-fold reduction in apparent affinity for 5-HT but complete loss of adenylyl cyclase stimulation. Binding of SB-258585 (4-iodo- -[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), a selective 5-HT antagonist, was mildly affected (2- to 4-fold decrease in affinity) in the two mutants. Our data suggest that Asp-72 and additional residues toward the intracellular side of TM II have a limited role in ligand binding but are critical for functional activation of the 5-HT receptor.
  • Is Part Of: European Journal of Pharmacology, 2006, Vol.534(1), pp.77-82
  • Identifier: ISSN: 0014-2999 ; E-ISSN: 1879-0712 ; DOI: 10.1016/j.ejphar.2006.01.049
  • Subjects: Site-Directed Mutagenesis ; Mouse 5-Ht 6 Receptor ; Pharmacy, Therapeutics, & Pharmacology
  • Language: English

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