Transcriptional Regulation of NMDA Receptor Expression

The N-methyl-D-aspartate (NMDA) subtypes of glutamate receptors are intimately involved in a number of important neuronal activities in mammalian nervous systems including neuronal migration, synaptogenesis, neuronal plasticity, neuronal survival, and excitotoxicity. Through these activities, NMDA receptors (NRs) play an important role in the development of drug addiction, pain perception, and the pathogenesis of neurological disorders such as schizophrenia and Huntington’s disease [1–10].

It is generally believed that aberrant or pathological NR effects occur mainly via abnormal receptor activity, resulting from altered availability of agonists or modified quality or quantity of membrane-associated receptors. In mammals, functional NRs are heterotetramers of subunits encoded by three gene families, i.e., NMDAR1 (NR1 or Grin1), NMDAR2 (NR2 or Grin2), and NMDAR3 (NR3 or Grin3) [3,4,11]. The NR1 family has one gene; the NR2 family has four (designated A through D); and the NR3 family has two (A and B). Structurally, NR1 is an essential component found in all tetramers, while different NR2 members are incorporated based on age and nervous system region. NR3 proteins function as negative components when included in the structures [3,4,11,12]. Eight variants of NR1 protein are produced by alternative splicing and distributed differentially in nervous systems [13–15]. This complex composition of different subunits and splicing variants forms the primary basis of the functional diversity of NRs.

From January 1992 to June 2007, more than 1000 research articles relevant to NR expression were published. In sum, they concluded that the expression of NR genes is cell- or tissue-specific, relatively stable, and regulated differentially by various physiological, pharmacological, and pathological factors. Most of these conclusions were based on assessments of changes of the steady state levels of mRNA and protein that may be driven by numerous sophisticated mechanisms. Transcription is the initial step and generally the most sensitive to cellular needs and environmental cues. Thus, it serves as a major mechanism controlling gene expression [16].

Precise spatial and temporal expression of a selective set of genes determines phenotypic differences among distinct tissues and cells in higher eukaryotes [16–18]. In the case of the NR gene families, transcription of each subunit gene in a given neuron or cell must be coordinately controlled but differentially responsive to cell type, developmental stage, and environmental signals to maintain healthy cellular function. How this coordinated control takes place is an important and challenging question. This chapter reviews studies that explore the transcriptional control of NR genes. It discusses studies of promoter and regulatory sequences, regulatory units, developmental regulation, cell type specificity, growth factor regulation, neurological disorders, and epigenetic mechanisms.