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- Title
Autocrine Activation of Neuronal NMDA Receptors by Aspartate Mediates Dopamine- and cAMP-Induced CREB-Dependent Gene Transcription.
- Authors
Almeida, Luis E. F.; Murray, Peter D.; Zielke, H. Ronald; Roby, Clinton D.; Kingsbury, Tami J.; Krueger, Bruce K.
- Abstract
cAMP can stimulate the transcription of many activity-dependent genes via activation of the transcription factor, cAMP response element-binding protein (CREB). However, in mouse cortical neuron cultures, prior to synaptogenesis, neither cAMP nor dopamine, which acts via cAMP, stimulated CREB-dependent gene transcription when NR2B-containing NMDA receptors (NMDARs) were blocked. Stimulation of transcription by cAMP was potentiated by inhibitors of excitatory amino acid uptake, suggesting a role for extracellular glutamate or aspartate in cAMP-induced transcription. Aspartate was identified as the extracellular messenger: enzymatic scavenging of L-aspartate, but not glutamate, blocked stimulation of CREB-dependent gene transcription by cAMP; moreover,cAMP induced aspartate but not glutamate release. Together, these results suggest that cAMP acts via an autocrine or paracrine pathway to release aspartate, which activates NR2B-containing NMDARs, leading to Ca2+ entry and activation of transcription. This cAMP/aspartate/NMDAR signaling pathway may mediate the effects of transmitters such as dopamine on axon growth and synaptogenesis in developing neurons or on synaptic plasticity in mature neural networks.
- Subjects
AUTOCRINE mechanisms; GLUTAMIC acid; CARRIER proteins; DOPAMINE; TRANSCRIPTION factors; NERVOUS system
- Publication
Journal of Neuroscience, 2009, Vol 29, Issue 40, p12702
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1166-09.2009