Staurosporine, K-252a, and K-252b stabilize calcium homeostasis and promote survival of CNS neurons in the absence of glucose

Abstract

Staurosporine, K-252a, and the 9-carboxylic related compound K-252b are low-molecular-weight alkaloids from microbial origin that at high concentrations are kinase inhibitors and can antagonize the effects of neuronal growth factors. Paradoxically, we have found that very low concentrations of these agents (10 fM-10 nM) prolong the survival of hippocampal, septal, and cortical neurons deprived of glucose. These agents did not prevent the depletion of ATP caused by glucose deprivation. The large elevation of intracellular calcium levels that normally mediates glucose deprivation-induced damage was attenuated by staurosporine, K-252a, and K-252b. Western blot analysis using antiphosphotyrosine antibody showed that staurosporine and the K-252 compounds (10-100 pM) stimulated tyrosine phosphorylation of several different proteins. The tyrosine kinase inhibitor genistein significantly reduced the protective effect of staurosporine and the K-252 compounds, indicating that tyrosine phosphorylation was required for neuroprotection by these compounds. Taken together, the data demonstrate that low concentrations of staurosporine and the K-252 compounds can stabilize calcium homeostasis, possibly by a mechanism involving activation of receptor tyrosine kinase transduction pathways.