Distinct localization of SAPK isoforms in neurons of adult mouse brain implies multiple signaling modes of SAPK pathway

Various cellular and environmental stresses lead to the activation of stress-activated protein kinase (SAPK), which is also referred to as c-Jun N-terminal kinase (JNK). In mammals, multiple SAPK isoforms, encoded by three independent genes, were identified. To gain insight into the roles of SAPK pathway in adult mouse brain, detailed expression patterns of three SAPK isoforms in brain were examined by using immunohistochemical and cell biological analyses. SAPKβ was heavily expressed in almost all regions of brain as previously reported. Interestingly, SAPKγ was also widely expressed at high levels. SAPKγ expression was generally overlapped with SAPKβ although there were some exceptions such as in hippocampus, where SAPKγ was restricted to CA3 and CA4 regions while SAPKβ was evenly expressed. SAPKα was widely expressed, but at low levels. It is particularly intriguing to note the differential subcellular localization of SAPK isoforms in neurons. In brain of normally reared mice, SAPKβ was identified in nucleus as well as in cytoplasm of neurons, while SAPKγ was detected mainly in cytoplasm and dendrites. Biochemical and immunological analyses revealed extraordinarily high basal activities of all SAPK isoforms in brain compared to peripheral organs, indicating that SAPK pathway may play a role in normal brain physiology. In addition, differential regional and subcellular localizations of SAPK isoforms allow us to speculate multiple signaling modes for SAPK activation in brain.ope