Ethanol inhibits brain-derived neurotrophic factor stimulation of extracellular signal-regulated/mitogen-activated protein kinase in cerebellar granule cells.
Brain-derived neurotrophic factor (BDNF) has emerged as a prominent mediator of neuronal development and synaptic plasticity. BDNF activates multiple signal transduction cascades that regulate cellular function through phosphorylation, transcription, and translation. Ethanol is known to inhibit neurotrophin signaling, but a thorough pharmacological analysis of the effect of ethanol on BDNF signaling in developing neurons has not been performed. These experiments were undertaken to determine the interactions between membrane depolarization, BDNF concentration, and ethanol concentration on extracellular signal-regulated protein kinase (ERK) activation in neurons. We examined cerebellar granule cells grown under physiological (5mM) or elevated (25mM) potassium culture conditions after 3 days in vitro. BDNF-stimulated ERK phosphorylation (pERK) within 10min and supported stimulation from 20 to 60min. Ethanol decreased basal pERK and reduced the magnitude of BDNF stimulation of ERK under both conditions. The NMDA receptor antagonist 2-amino-5-phosphonovalerate did not effect basal pERK or inhibit BDNF stimulation of ERK, suggesting that NMDA receptors do not modulate BDNF stimulation of ERK in short-term cultures. These data characterize the pharmacological effects of ethanol on growth factor signaling and provide the basis of a model for further characterization of the biochemical mechanisms of ERK inhibition by ethanol. Perturbation of BDNF signal transduction by ethanol may underlie some of the cognitive deficits and developmental abnormalities resulting from ethanol exposure.
Ohrtman
Joshua D
JD
Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fisher's Lane MSC 9411, Bethesda, MD 20892-9411, USA.
Stancik
Elizabeth K
EK
Lovinger
David M
DM
Davis
Margaret I
MI
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D000431:Ethanol; D048049:Extracellular Signal-Regulated MAP Kinases