Binding properties of the naturally occurring human 5-HT_1A receptor variant with the Ile28Val substitution in the extracellular domain

The cDNA from a schizophrenic patient heterozygous for a mutation of the 5-HT_1A 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-HT_1A receptor. The potencies of the 5-HT_1A 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-HT_1A receptor were determined. All five 5-HT_1A receptor ligands concentration-dependently inhibited specific [³H]8-OH-DPAT binding to both the wild-type and the variant 5-HT_1A 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-HT_1A 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 wild-type receptor (r = 0.995). It is concluded that the pharmacological profile of the mutant 5-HT_1A receptor does not differ from that of the wild-type 5-HT_1A receptor.