Autocrine activation of neuronal NMDA receptors by aspartate mediates dopamine- and cAMP-induced CREB-dependent gene transcription.
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.
Almeida
Luis E F
LE
Department of Physiology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Murray
Peter D
PD
Zielke
H Ronald
HR
Roby
Clinton D
CD
Kingsbury
Tami J
TJ
Krueger
Bruce K
BK
D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D019898:Autocrine Communication / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D018929:Cell Culture Techniques; D002540:Cerebral Cortex / Q000196:embryology / Q000502:physiology; D005576:Colforsin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D015220:Calcium Channels; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C529585:Gapex-5 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D005576:Colforsin; D001224:Aspartic Acid; D000242:Cyclic AMP; D002118:Calcium; D004298:Dopamine