The Journal of Neuroscience, January 25, 2006, 26(4):1065-1076; doi:10.1523/JNEUROSCI.3347-05.2006
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Cellular/Molecular
Splice Variants of the NR1 Subunit Differentially Induce NMDA Receptor-Dependent Gene Expression
John Bradley,1
Sarah R. Carter,1,3
Vikram R. Rao,1,4
Jun Wang,1 and
Steven Finkbeiner1,2,3,4
1Gladstone Institute of Neurological Disease, 2Departments of Neurology and Physiology and the 3Neuroscience and 4Biomedical Science Programs, University of California, San Francisco, San Francisco, California 94141
Correspondence should be addressed to Steven Finkbeiner, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: sfinkbeiner{at}gladstone.ucsf.edu
Subunits of the NMDA receptor (NMDAR) associate with many postsynaptic proteins that substantially broaden its signaling capacity. Although much work has been focused on the signaling of NR2 subunits, little is known about the role of the NR1 subunit. We set out to elucidate the role of the C terminus of the NR1 subunit in NMDAR signaling. By introducing a C-terminal deletion mutant of the NR1 subunit into cultured neurons from NR1/ mice, we found that the C terminus was essential for NMDAR inactivation, downstream signaling, and gene expression, but not for global increases in intracellular Ca2+. Therefore, whereas NMDARs can increase Ca2+ throughout the neuron, NMDAR-dependent signaling, both local and long range, requires coupling through the NR1 C terminus. Two major NR1 splice variants differ by the presence or absence of a C-terminal domain, C1, which is determined by alternative splicing of exon 21. Analysis of these two variants showed that removal of this domain significantly reduced the efficacy of NMDAR-induced gene expression without affecting receptor inactivation. Thus, the NR1 C terminus couples to multiple downstream signaling pathways that can be modulated selectively by RNA splicing.
Key words: NMDA receptor; NR1 subunit; alternative splicing; gene expression; calcium; CREB
Received Aug. 9, 2005;
revised Nov. 29, 2005;
accepted Nov. 30, 2005.
Correspondence should be addressed to Steven Finkbeiner, Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158. Email: sfinkbeiner{at}gladstone.ucsf.edu
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