Neuronal survival induced by neurotrophins requires calmodulin

It has been reported that phosphoinositide 3-kinase (PI 3-kinase) and its d ownstream target, protein kinase B (PKB), play a central role in the signal ing of cell survival triggered by neurotrophins (NTs). In this report, we h ave analyzed the involvement of Ca2+ and calmodulin (CaM) in the activation of the PKB induced by NTs. We have found that reduction of intracellular C a2+ concentration or functional blockade of CaM abolished NGF-induced activ ation of PKB in PC12 cells. Similar results were obtained in cultures of ch icken spinal cord motoneurons treated with brain-derived neurotrophic facto r (BDNF). Moreover, CaM inhibition prevented the cell survival triggered by NGF or BDNF This effect was counteracted by the transient expression of co nstitutive active forms of the PKB, indicating that CaM regulates NT-induce d cell survival through the activation of the PKB. We have investigated the mechanisms whereby CaM regulates the activation of the PKB, and we have fo und that CaM was necessary for the proper generation and/or accumulation of the products of the PI 3-kinase in intact cells.