Binding properties of the naturally occurring human 5-HT1A receptor variant with the Ile28Val substitution in the extracellular domain.
The cDNA from a schizophrenic patient heterozygous for a mutation of the 5-HT1A receptor gene was used to clone the variant and wild-type DNA into a eukaryotic expression vector. The mutation was characterized by a base pair substitution (A --> G) at the first position of codon 28, leading to an Ile --> Val amino acid exchange. COS-7 cells were transfected with the cDNA of either the wild type or the variant 5-HT1A receptor. The potencies of the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetraline (8-OH-DPAT), 5-HT and roxindole, and of the antagonists methiothepin and spiperone in inhibiting specific binding of [3H]8-OH-DPAT of the mutant and wild-type 5-HT1A receptor ligands concentration-dependently inhibited specific [3H]8-OH-DPAT binding to both the wild-type and the variant 5-HT1A receptor. The rank order of potency of the ligands in inhibiting [3H]8-OH-DPAT binding was identical at both receptors and was roxindole > 8-OH-DPAT > 5-HT> methiothepin > spiperone. This rank order is characteristic for 5-HT1A receptors. The negative logarithms of the concentrations required for 50% inhibition (pIC50 values) of the ligands at the mutant 5-HT receptor correlated highly significantly with those at the wildtype receptor (r = 0.995). It is concluded that the pharmacological profile of the mutant 5-HT1A receptor does not differ from that of the wild-type 5-HT1A receptor.
Brüss
M
M
Institut für Pharmakologie und Toxikologie, Universität Bonn, Germany.
Bühlen
M
M
Erdmann
J
J
Göthert
M
M
Bönisch
H
H
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D001483:Base Sequence; D002478:Cells, Cultured; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011985:Receptors, Serotonin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011985:Receptors, Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin