RESUMO
Influx of Ca(2+) ions through the α-amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptors is toxic to neurons and contributes to motor neuron degeneration observed in amyotrophic lateral sclerosis (ALS). The Ca(2+) permeability of the AMPA receptor depends on its subunit composition. If the GluR2 subunit is present in the receptor complex, the AMPA receptor is impermeable to Ca(2+). In this study, we identified vascular endothelial growth factor-A (VEGF) as a GluR2 inducing molecule. Cultured motor neurons pretreated with VEGF displayed higher GluR2 levels. This resulted in AMPA receptor currents with a low relative Ca(2+) permeability and in motor neurons that were less vulnerable to AMPA receptor-mediated excitotoxicity. This effect of VEGF was mediated through the VEGFR2 present on the motor neurons and was due to stimulation of GluR2 transcription. Intracerebroventricular treatment with VEGF similarly induced GluR2 expression in the ventral spinal cord of rats and this mechanism contributes to the protective effect of VEGF on motor neurons.
Assuntos
Neurônios Motores/metabolismo , Degeneração Neural/terapia , Neurotoxinas/antagonistas & inibidores , Receptores de AMPA/biossíntese , Regulação para Cima/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Células Cultivadas , Técnicas de Cocultura , Injeções Intraventriculares/métodos , Neurônios Motores/fisiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Neurotoxinas/farmacologia , Ratos , Ratos Wistar , Receptores de AMPA/genética , Receptores de AMPA/fisiologia , Medula Espinal/citologia , Medula Espinal/metabolismo , Medula Espinal/fisiologia , Fator A de Crescimento do Endotélio Vascular/administração & dosagemRESUMO
Influx of Ca(2+) ions through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors contributes to neuronal damage in stroke, epilepsy, and neurodegenerative disorders such as ALS. The Ca(2+) permeability of AMPA receptors is largely determined by the glutamate receptor 2 (GluR2) subunit, receptors lacking GluR2 being permeable to Ca(2+) ions. We identified a difference in GluR2 expression in motor neurons from two rat strains, resulting in a difference in vulnerability to AMPA receptor-mediated excitotoxicity both in vitro and in vivo. Astrocytes from the ventral spinal cord were found to mediate this difference in GluR2 expression in motor neurons. The presence of ALS-causing mutant superoxide dismutase 1 in astrocytes abolished their GluR2-regulating capacity and thus affected motor neuron vulnerability to AMPA receptor-mediated excitotoxicity. These results reveal a mechanism through which astrocytes influence neuronal functioning in health and disease.