| Biological systems in higher organisms are comprised of highly interactive networks that involve multiple genetic and environmental elements. Allergic asthma and brain edema represent disorders in two such complex systems that are only partially understood, namely the immune system and the central nervous system. To identify genes influencing the development of allergic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum IgE concentration. Sib-pair and transmission disequilibrium analyses in Afro-Caribbean and Caucasian families revealed linkage of these loci to both asthma and the associated “high IgE” trait, suggesting that this region contains a gene(s) controlling allergic asthma.; To identify factors involved in brain edema, we investigated the mechanisms regulating expression of the aquaporin-4 (AQP4) water channel in astrocytes surrounding brain blood vessels. Four AQP4 polypeptides corresponding to two isoforms differing at their N-termini were identified in brain and multiple other rat tissues. The 34 and 38 kDa polypeptides represent the longer and more abundant “M1” isoform, and 32 and 36 kDa correspond to the shorter “M23” isoform. AQP4 water channels in rat brain are comprised predominantly of M1/M23 heterotetramers, with some M23 homotetramers, reflecting the relative expression levels of the two isoforms. We further show that AQP4 water channels in brain are associated with a perivascular complex that contains syntrophin and the 71 kDa dystrophin isoform Dp71. Analyses of α-syntrophin −/− mice and AQP4-transfected cell lines indicate that this association promotes AQP4 plasma membrane retention and may be mediated by the interaction of the AQP4 C-terminus with the syntrophin PDZ domain. We also show that expression of AQP4 in astrocytes, like that of Dp71, is upregulated by cAMP. These findings provide a mechanism for matching the expression of AQP4 in brain with that of a complex regulating its retention in astrocyte membrane regions that contact blood vessels. Our inability to detect changes in AQP4 expression following cerebral ischemia suggests that hypoxia/ischemia-induced alterations in AQP4-containing membrane assemblies may involve regional changes in expression or changes in post-translational regulation of AQP4 tetramers at the plasma membrane. |
