Identification of single-nucleotide polymorphisms of the human neurokinin 1 receptor gene and pharmacological characterization of a Y192H variant

Abstract

Neurokinin receptors in the central nervous system are involved in the neural circuitry of anxiety, depression and emesis. This has led to the development of nonpeptidic NK1 receptor antagonists as therapeutic agents. Clinical trials have shown that NK1 receptor antagonists have efficacy in chemotherapy-induced emesis and depression. Sequence polymorphisms can potentially influence the efficacy of drugs in patient populations and are an important consideration in the drug development process. To identify DNA sequence variants in the NK1 receptor, comparative DNA sequencing was performed on a population of 93 individuals. In total, 19 single-nucleotide polymorphisms (SNPs) were identified with one SNP (g.78351T>C) resulting in a tyrosine to histidine substitution at residue 192 (Y192H). The Y192H variant was expressed using site-directed mutagenesis and was characterized with respect to affinity, receptor kinetics, functional calcium response and receptor internalization. In all cases the Y192H variant was found to display properties similar to those of the wild-type receptor.