Role of soluble adenylyl cyclase in ischemia-reperfusion-induced brain injury

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Ischemic stroke is an acute neurodegenerative disorder that is one of the leading causes of death and disability. Increasing evidence suggest that apoptosis contributes significantly in the neuronal death under cerebral ischemia-reperfusion. Within several signaling pathways, cAMP-PKA signaling plays an essential role in modulating the apoptotic response to different stress stimuli including ischemic insult. Until now, it was attributed exclusively to the activity of the G-protein-responsive transmembrane adenylyl cyclase (tmAC). Aside from the tmAC, mammalian cells possess a second source of cAMP, the ubiquitously expressed soluble adenylyl cyclase (sAC). Recently, we demonstrated that this cyclase is an essential modulator of mitochondria-dependent apoptosis in coronary endothelial cells. Furthermore, we found that the active form of this cyclase is also expressed in rat cortex. Whether sAC contributes in apoptosis of neuronal cells is unknown. To investigate the role of sAC in cerebral apoptosis induced by ischemia-reperfusion is the aim of the proposed project. For this purpose, first in vitro studies with primary rat embryonic cell culture as well as with human neuroblastoma culture exposed to simulated ischemia-reperfusion will be performed. Finally, in vivo studies with wild type or sAC-knockout mice will be curried out.