Functional consequences of $IP_3$ receptor polymorphism

Abstract

Anxiety in mice can be measured by behavioral reactivity to social or non-social stressors. These behaviors were compared by performing the resident-intruder test (social) as well as the light-dark transition and open-field tests (non-social) for the FVB, C57BL/6, and BALB/c lines of mouse. The three inbred lines showed significant differences in their responses to intruder mice. In order to obtain common factors, a principal component analysis was performed. Three factors, accounting for about 68 % of the total variance, were extracted from the scores obtained from the three behavioral tests. The first two major factors are primarily associated with the anxiety-related behaviors. One includes anxiety behaviors with a locomotive basis, while the other includes defecation measured in both anxiety tests. The third factor explains the three social behaviors, facial investigation, ano-genital investigation, and following, observed in the resident intruder test, although facial investigation is also moderately associated with the second factor. The results indicate that the behavioral responses to an intruder share a component distinct from anxiety-related behaviors. BALB/c mice showed a higher defecation than C57BL/6 under stress condition. Inositol 1,4,5-trisphosphate receptor $(IP_3R)$ regulates defecation rhythm in C.elegans. Thus, in order to investigate that the phenotypic variation is associated with functional differences of $Type 3 IP_3R (IP_3R3)$, which is major $IP_3R$ isofrom in the intestine, polymorphism was searched. Here, the natural $Pro^{335}Leu$ polymorphism of mouse $IP_3R_3$ was found between BABL/c and C57BL/6J. The functional differences between $Pro^{335}IP_3R_3$ and $Leu^{335}IP_3R_3$ were investigated with purified receptors reconstituted into proteoliposomes as well as with soluble ligand binding domains (LBDs). $Pro^{335}IP_3R_3$ exhibited significantly higher $IP_3-binding$ affinity and $IP_3-induced Ca^{2+}$ release than those of $Leu^...