Effects of mutations at conserved TM II residues on ligand binding and activation of mouse 5-HT6 receptor.
Eur J Pharmacol
; 534(1-3): 77-82, 2006 Mar 18.
Article
em En
| MEDLINE
| ID: mdl-16612839
ABSTRACT
An aspartate residue (Asp-72) in the transmembrane helix II of mouse 5-hydroxytryptamine-6 receptor (5-HT6) 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 EC50 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-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), a selective 5-HT6 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-HT6 receptor.
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Base de dados:
MEDLINE
Assunto principal:
Receptores de Serotonina
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article