Human GRIN3B blocking peptide

NR3B is a modulatory subunit of the NMDA receptor, abundantly expressed in both cranial and spinal somatic motoneurons and at lower levels in other regions of the brain as well. Recently, we found the human NR3B gene (GRIN3B) to be highly genetically heterogeneous, and that similar to 10% of the normal European-American population lacks NR3B due to homozygous occurrence of a null allele in the gene. Therefore, it is especially important to understand the phenotypic consequences of the genetic loss of NR3B in both humans and animal models. We here provide results of behavioral analysis of mice genetically lacking NR3B, which is an ideal animal model due to homogeneity in genetic and environmental background. The NR3B(-/-) mice are viable and fertile. Consistent with the expression of NR3B in somatic motoneurons, the NR3B(-/-) mice showed a moderate but significant impairment in motor learning or coordination, and decreased activity in their home cages. Remarkably, the NR3B(-/-) mice showed a highly increased social interaction with their familiar cage mates in their home cage but moderately increased anxiety-like behaviour and decreased social interaction in a novel environment, consistent with the inhibitory role of NR3B on the functions of NMDA receptors. This work is the first reporting of the functional significance of NR3B in vivo and may give insight into the contribution of genetic variability of NR3B in the phenotypic heterogeneity among human population.

Growing amounts of evidence suggest that N-Methyl-n-aspartate (NMDA) receptor mediated glutamate neurotransmission may be involved in the pathophysiology of drug dependence. The NMDA receptor consists of three subfamilies (NR1, NR2, and NR3). The ability of subunit NR3 to negatively modulate the NMDA receptor function makes it an attractive candidate gene of heroin addiction. The purpose of this study is to explore the association between four single nucleotide polymorphisms (SNPs) of NR3 gene and heroin addiction. Genotyping of two SNPs (rs3739722 and rs17189632) in GRIN3A and two SNPs (rs4807399 and rs2240158) in GRIN3B was performed using TaqMan SNP genotyping method. The association between heroin addiction and these SNPs was assessed among 332 male heroin dependent patients and 400 male normal control subjects. The results showed the genotype and allele frequencies of rs17189632 and rs2240158 were significantly different between the cases and the controls (nominal P values were 0.0284, 0.0136 for rs17189632; 0.0048, 0.0013 for rs2240158, respectively). After Bonferroni correction, rs2240158 of GRIN3B was still found to be associated with heroin addiction. The frequencies of haplotype C-A at GRIN3A (rs3739722-rs17189632) and of C-C and C-T at GRIN3B (rs4807399-rs2240158) differed significantly between the cases and the controls. The genotype and allele distributions of rs3739722 and rs4807399 were not significantly different between in the cases and in the controls (P>0.05). These results suggest that GRIN3A rs17189632 and GRIN3B rs2240158 may contribute to the susceptibility of heroin addiction. (C) 2016 Elsevier Ireland Ltd. All rights reserved.