Understanding NMDA receptors
Understanding NMDA receptors; key targets for therapeutic intervention in disorders of the Central Nervous System
By F Anne Stephenson, School of Pharmacy, University of London
The fidelity of synaptic function in the brain is dependent on the expression of the appropriate neurotransmitter receptor subtype, the targeting and trafficking of these receptors to synapses as well as the regulation of the actual number of receptors at synapses.
The family of N-methyl-D-aspartate (NMDA) receptors are a subclass of the excitatory, ionotropic L-glutamate neurotransmitter receptors. NMDA receptors are important for normal brain function being both primary candidates for the molecular basis of learning and memory and in the establishment of synaptic connections during the development of the central nervous system.
NMDA receptors are also implicated in neurological, neurodegenerative and psychiatric disorders. Their dysfunction which is primarily due to either hypo- or hyper-activity is pivotal to these pathological conditions. There is thus a fine balance between NMDA receptor-mediated mechanisms in normal brain and in diseased states where receptor homeostasis is perturbed.
NMDA receptors are activated by the co-agonists, L-glutamate and glycine, the alleviation of a voltage-dependent magnesium blockade by activation of adjacent non-NMDA glutamate receptors resulting in the opening of an integral ion channel with a high permeability for calcium ions.
There are seven genes encoding NMDA receptor subunits. Functional NMDA receptors are hetero-tetrameric integral membrane proteins being composed of the obligatory NR1 glycine binding subunit assembled with different combinations of NR2 and NR3 NMDA receptor subunits to yield receptors with distinct biophysical and pharmacological properties. Receptor activity is due in part to the number of surface expressed receptors.
NMDA receptors are localized at excitatory synapses. These synapses are highly structured but dynamic with interplay between NMDA receptors and NMDA receptor associated scaffolding proteins regulating the expression of functional cell surface synaptic and extra-synaptic receptors. Understanding the assembly and trafficking of this complex, heteromeric, neurotransmitter receptor family may therefore be pivotal to understanding diseases in which their altered activity is evident.
This lecture will describe studies from my research group that have generated highly specific antibody research reagents that have led to the elucidation of the subunit compositions of the major NMDA receptor subtypes, the contribution of the post-synaptic density-95 (PSD-95) membrane associated guanylate kinase (MAGUK) family of scaffold proteins to the organization and lateral mobility of NMDA receptors at synapses and, key regulatory steps in the assembly and cell surface trafficking of receptors. Finally,
I will describe our most recent work in which we have discovered a novel protein-protein interaction between NMDA receptors and amyloid precursor protein (APP), mutations of which have been strongly linked to familial forms of Alzheimer’s disease.
Despite intense study, the physiological function of APP remains unknown. One proposed role for APP is the regulation of neuronal trafficking. We have shown that APP may contribute to postsynaptic mechanisms via the regulation of the surface trafficking of key subtypes of NMDA receptors thus yielding new insights into the function of APP and possibly, new avenues to explore for the generation of novel therapeutic agents for the treatment of dementia.
The research in my laboratory is supported by the BBSRC (UK); The Alzheimer’s Research Trust; the Medical Research Council (UK) and The Wellcome Trust.