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 chemotherapyinduced 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.78351T4C) resulting in a tyrosine to histidine subsitution 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.

Susceptibility Locus in Neurokinin-1 Receptor Gene Associated with Alcohol Dependence

“…In the AD sample, allele A of rs6715729 was significantly more frequent than that in the control sample. The frequency of the A allele in our control sample was in agreement with the findings of an independent study by Randolph et al (2004) that showed the A allele of rs6715729 to be less frequent than the G allele in a sample of 100 healthy individuals of Caucasian descent.…”

“…In a cohort of German subjects, Giegling et al (2007) showed that four SNPs located across NK1R were not associated with suicidal behavior but may modulate aggression features. Nominal associations were found with panic disorder (Hodges et al , 2009) and bipolar disorder (Perlis et al , 2008); lack of an association of NK1R SNPs was reported with autism (Marui et al , 2007) and dyslexia (Peyrard-Janvid et al , 2004). To our knowledge, associations of NK1R polymorphisms with any substance use disorders have not been examined.…”

“…The biological actions of SP are exerted primarily through neurokinin receptor subtype 1 (NK1R; also called tachykinin receptor 1; TACR1), which is densely expressed in the brain structures implicated in stress pathways (Giegling et al , 2007), as well as in non-neuronal peripheral tissues including gut, joints, muscle, and cutaneous tissues (Santarelli et al , 2001; Almeida et al , 2004). Antagonists of NK1R are effective in treating depression, anxiety, and post-operative and chemotherapy-induced emesis (Randolph et al , 2004). Recently, a reduction in the craving for alcohol in anxious alcoholics was reported in response to the NK1R blocker LY686017 (George et al , 2008).…”

Neurokinin 1 receptor isoforms and the control of innate immunity

“…Two N-linked glycosylation sites, Asparagine-14 and Asparagine-18 have been described in full length NK1R, although they might not have an important role for receptor function [48]. A single polymorphism in the human neurokinin-1 receptor gene has been identified [49]; this is the Y192H variant, which displays affinity, receptor kinetics, functional calcium response and receptor internalization properties similar to the wild type variant [49]. Box 1.…”

Truncation of neurokinin-1 receptor—Negative regulation of substance P signaling

“…NK1R is encoded by the TACR1 gene, which, in humans, is 1,221 nucleotides long and consists of 5 exons . The NK1R‐T isoform is produced by retention of the fourth intron in the mature mRNA transcript resulting in the introduction of a premature stop codon at the end of exon 4 and before the start of exon 5 (Fig.…”