Rabbit Anti-Human ADCY8 (a.a. 151-250) Polyclonal antibody

Our group first reported a linkage finding for bipolar ( BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta = 0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'common disease - common variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha = 0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).

Adenylyl cyclase 8 (ADCY8) and Farnesoid X Receptor (FXR) have been identified in pancreatic beta-cells and play important roles in insulin secretion. But the mechanisms underlying with respect to the regulation of ADCY8 expression in beta-cells, particularly whether FXR is involved, remain unexplored. We now show that ADCY8 expression is decreased in Goto-Kaldzald (GK) rat islets compared with healthy Wistar controls. We also found that reduced ADCY8 is associated with decreased expression of FXR. Consistently, ADCY8 expression was suppressed by the knockdown of FXR in INS-1 832/13 cells, as well as the islets from FXR knockout mice. On the contrary, ADCY8 expression was increased in FXR-overexpressed INS-1 832/13 cells or in the case of FXR activation. Mechanistically, FXR directly binds to Adcy8 promoter and recruits the histone acetyltransferase Steroid Receptor Coactivator 1 (SRC1), thereby resulting in the increased acetylation of histone H3 in Adcy8 locus, promoting Adcy8 gene transcription in beta-cells. Thus, this study indicates that FXR is a critical transcription factor that mediates ADCY8 expression in pancreatic beta-cells and has characterized the chromatin modification associated with Adcy8 transcription.