Neuronal Survival Induced by Neurotrophins Requires Calmodulin

• Published in: The Journal of cell biology Vol. 154; no. 3; pp. 585 - 597
• Main Authors: Egea, Joaquim, Espinet, Carme, Soler, Rosa M., Dolcet, Xavier, Yuste, Víctor J., Encinas, Mario, Iglesias, Montserrat, Rocamora, Nativitat, Comella, Joan X.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 06.08.2001; The Rockefeller University Press
• Subjects: Animals; Apoptosis; Brain-Derived Neurotrophic Factor - pharmacology; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Calmodulin - antagonists & inhibitors; Calmodulin - metabolism; Cell Membrane - metabolism; Cell membranes; Cell nucleus; Cell Survival - drug effects; Cell Survival - physiology; Cells; Cellular biology; Chelating Agents - pharmacology; Chromones - pharmacology; Cultured cells; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Enzyme Inhibitors - pharmacology; Enzymes; Green Fluorescent Proteins; Indicators and Reagents - metabolism; Luminescent Proteins - genetics; Memory interference; Morpholines - pharmacology; Nerve Growth Factor - pharmacology; Nervous system; Neurons; Neurons - cytology; Neurons - enzymology; PC12 Cells; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositols; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Rats; Recombinant Proteins - metabolism; Signal Transduction - physiology; Spinal cord; Sulfonamides - pharmacology
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200101023

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