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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 Finkbeiner^1,2,3,4

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

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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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