Modified ligand binding to the naturally occurring Cys-124 variant of the human serotonin 5-HT1B receptor

A substitution of phenylalanine by cysteine in position 124 is the only kno wn naturally occurring variant of the human 5-HT1B (h5-HT1B) receptor. The present study was designed to evaluate the potential influence of the Cys-1 24 variant on pharmacological properties of the receptor and to test for an involvement of the mutation in the genetic predisposition to schizophrenia or bipolar affective disorder, Binding of [H-3]5-carboxamidotryptamine ([H -3]5-CT) and its competition with serotonin receptor agonists and antagonis ts were determined in COS-7 cells transfected with the wild-type or the var iant h5-HT1B receptor cDNA, In saturation experiments with [H-3]5-CT, the m aximum binding (B-max) of the variant receptor was approximately 30% of the wild-type receptor. In competition experiments with 1 nM [H-3]5-CT, the fo llowing serotonin receptor ligands exhibited a two to three times higher af finity for the mutant than for the wild-type receptor: dihydroergotamine, L -694,247, SB-216641, 5-CT, 5-HT, sumatriptan, RU24969 and methysergide (com pounds listed at decreasing order of potency at the wild-type receptor). In contrast, the serotonin receptor antagonist ketanserin exhibited higher bi nding affinity for the wild-type than for the mutant h5-HT1B receptor and G R127939, (-)propranolol and BRL-15572 showed equal affinity for both types of receptor. Mutation screening of schizophrenic and bipolar patients revea led no relationship between the variant receptor and development of disease . In conclusion, our data suggest that the Cys-124 variant significantly af fects the pharmacological properties of the h5-HT1B receptor. Carriers of t he variant may exhibit differences in response to drugs acting on the h5-HT 1B receptor or may develop side-effects to such agents, Pharmacogenetics 9: 95-102 (C) 1999 Lippincott Williams & Wilkins.