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Abstract
For years, GluN3A was solely considered to be a dominant-negative modulator of NMDARs, since its incorporation into receptors alters hallmark features of conventional NMDARs composed of GluN1/GluN2 subunits. Only recently, increasing evidence has accumulated that GluN3A plays a more diversified role. It is considered to be critically involved in the maturation of glutamatergic synapses, and it might act as a molecular brake to prevent premature synaptic strengthening. Its expression pattern supports a putative role during neural development, since GluN3A is predominantly expressed in early pre- and postnatal stages. In this study, we used RNA interference to efficiently knock down GluN3A in 46C-derived neural stem cells (NSCs) both at the mRNA and at the protein level. Global gene expression profiling upon GluN3A knockdown revealed significantly altered expression of a multitude of neural genes, including genes encoding small GTPases, retinal proteins, and cytoskeletal proteins, some of which have been previously shown to interact with GluN3A or other iGluR subunits. Canonical pathway enrichment studies point at important roles of GluN3A affecting key cellular pathways involved in cell growth, proliferation, motility, and survival, such as the mTOR pathway. This study for the first time provides insights into transcriptome changes upon the specific knockdown of an NMDAR subunit in NSCs, which may help to identify additional functions and downstream pathways of GluN3A and GluN3A-containing NMDARs.
Highlights
Ever since its discovery in 1995, the N-methyl-D-aspartate receptor (NMDAR) subunit GluN3A was considered to be a dominant-negative regulator of NMDARs by abolishing their Mg2+ block and by reducing their Ca2+ permeability and current responses [1,2,3,4,5]
Besides a variety of pathways involved in cell growth, proliferation, motility, and survival being significantly affected by the GluN3A knockdown, we found that the mRNA expression of several neural genes is affected by the knockdown of GluN3A
GluN3A transcripts were expressed in all 46C-derived cell types, even weakly in undifferentiated embryonic stem cell (ESC)
Summary
Ever since its discovery in 1995, the N-methyl-D-aspartate receptor (NMDAR) subunit GluN3A was considered to be a dominant-negative regulator of NMDARs by abolishing their Mg2+ block and by reducing their Ca2+ permeability and current responses [1,2,3,4,5]. Evidence for a more diverse role of the GluN3 subunits than being down-regulators of NMDAR function has accumulated. GluN3 was suggested to support the developmental switch from GluN2B and GluN2D (prenatally) to GluN2A and GluN2C subunits (postnatally) [10, 11] via the interaction with PACSIN1 (protein kinase C and casein kinase substrate in neurons protein 1), which is involved in clathrin-mediated endocytosis and actin rearrangement [12]. Immature GluN1/GluN2B/ GluN3A triheteromers are rapidly removed from glutamatergic synapses, undergoing endocytosis and transport to early endosomes, a process which relies on the interaction of GluN3A with PACSIN1 [12]. It was suggested that the incomplete removal of juvenile GluN3A-containing NMDARs might contribute to the pathophysiology of Huntington’s disease [14, 15]
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