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Neuronal survival induced by neurotrophins requires calmodulin
1Grup de Neurobiologia Molecular, Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, 25198 Lleida, Catalonia, Spain.
Abstract:
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.
Insights
Calcium and calmodulin are crucial for neurotrophin-induced cell survival signaling. These molecules activate protein kinase B (PKB) by enabling phosphoinositide 3-kinase (PI 3-kinase) activity, thereby promoting cell survival.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Signaling
Background:
- Neurotrophins (NTs) signal cell survival via phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB).
- The precise role of calcium (Ca2+) and calmodulin (CaM) in this pathway remains to be fully elucidated.
Purpose of the Study:
- To investigate the involvement of Ca2+ and CaM in NT-induced PKB activation and cell survival.
- To understand the mechanism by which CaM regulates PKB activation.
Main Methods:
- Utilized PC12 cells and chicken spinal cord motoneurons.
- Administered nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF).
- Manipulated intracellular Ca2+ levels and blocked CaM function; employed constitutive active PKB expression.
Main Results:
- Reduced intracellular Ca2+ or CaM blockade abolished NGF-induced PKB activation in PC12 cells.
- Similar effects were observed with BDNF in motoneurons.
- CaM inhibition prevented NT-induced cell survival, an effect reversed by active PKB expression.
- CaM is essential for PI 3-kinase product generation/accumulation.
Conclusions:
- Ca2+ and CaM are indispensable for NT-induced PKB activation and subsequent cell survival.
- CaM regulates NT-mediated cell survival by activating PKB.
- CaM's mechanism involves facilitating PI 3-kinase activity, upstream of PKB.