Autocrine Activation of Neuronal NMDA Receptors by Aspartate Mediates Dopamine- and cAMP-Induced CREB-Dependent Gene Transcription

• Published in: The Journal of neuroscience 2009-10, Vol.29 (40), p.12702-12710
• Main Authors: Almeida, Luis E. F, Murray, Peter D, Zielke, H. Ronald, Roby, Clinton D, Kingsbury, Tami J, Krueger, Bruce K
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Aspartic Acid - metabolism; Autocrine Communication - physiology; Brain-Derived Neurotrophic Factor - genetics; Calcium - metabolism; Calcium Channels - metabolism; Cell Culture Techniques; Cerebral Cortex - embryology; Cerebral Cortex - physiology; Colforsin - metabolism; Cyclic AMP - metabolism; Cyclic AMP Response Element-Binding Protein - metabolism; Dopamine - metabolism; Guanine Nucleotide Exchange Factors - genetics; Mice; Molecular Sequence Data; Neuronal Plasticity - physiology; Neurons - physiology; Phosphorylation; Proto-Oncogene Proteins c-fos - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Transcription, Genetic - physiology; Transcriptional Activation - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1166-09.2009

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 Ca(2+) 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.