Hypoxia regulates the cAMP- and Ca2+/calmodulin signaling systems in PC12 cells

Hypoxic/ischemic trauma is a primary factor in the pathology of various disease states. Yet, very little is known about the molecular mechanisms involved in cellular responses and adaptations to hypoxia. As a means of identifying intracellular signaling systems that are regulated in response to hypoxia, the effects of acute and chronic hypoxia on the activity of protein kinase A (PKA) and Ca2+/CaM-dependent protein kinase II (CaMK-II) were evaluated in rat pheochromocytoma (PC12) cells. Chronic (> 6 hr), but not acute exposure to hypoxia (5% O2) significantly decreased both PKA enzyme activity and immunoreactivity compared to control levels. This effect was not due to hypoxia-induced alterations in cell number or viability. Similarly, chronic hypoxia significantly decreased CaMK-II enzyme activity and protein levels in PC12 cells. These data demonstrate that down-regulation of the cAMP and Ca2+/CaM-signaling systems is a mechanism by which PC12 cells adapt to long-term hypoxia.