Abstract
NMDA receptor channels play a significant role in learning and memory and their dysfunction can cause neuronal cell death leading to dementia. Research had shown that lipids change the risk for dementia, especially some omega-3 lipids appear to lower Alz-heimer’s risk, yet only limited research exists on the modulation of NMDA receptor channels by lipids. Here we review recent literature concerning molecular determinants that influence the NMDA receptor channel gating via membrane lipids and fatty acids with profound significance for understanding how altered NMDA signalling leads to neuronal cell death linked to age-related dementia’s. Future discovery of lipid-like modulators of NMDA receptor function offer the potential for the development of new bioceu-ticals and affordable nutritional supplements to combat neuronal degeneration as well as to promote well being and healthy aging.
Highlights
The NMDA receptor is an oligomeric cation channel which mediates long-term potentiation, synaptic plasticity and neuro-degeneration via conditional Ca2+ signalling [1,2,3]
NMDA receptor channels play a significant role in learning and memory and their dysfunction can cause neuronal cell death leading to dementia
Research had shown that lipids change the risk for dementia, especially some omega-3 lipids appear to lower Alzheimer’s risk, yet only limited research exists on the modulation of NMDA receptor channels by lipids
Summary
The NMDA receptor is an oligomeric cation channel which mediates long-term potentiation, synaptic plasticity and neuro-degeneration via conditional Ca2+ signalling [1,2,3]. The complexity of NMDA receptors arises from multiple genes encoding different subunits of the channel and alternative splicing of mRNA, which determines the variability in subunit composition, as well as functional heterogeneity. Underlined are clusters of charged residues proposed to act as a lipid sensor; (c) Reconstituted NMDA receptor NR1 into Giant Unilammelar Vesicles (GUVs) prepared with Vesicle-Prep-Pro (Nanion technologies) form functional homomeric channel activated by agonists. The transmembrane topology of NMDA receptor proteins predicts an extracellular N-terminus, followed by three transmembrane domains (TM1 - TM3) and intracellular C-terminus (Figure 1(a)). In the postnatal and adult brain, NMDA receptors act as molecular coincidence detectors of presynaptic and postsynaptic activity facilitated by pre-synaptic release of glutamate and simultaneous depolarization of the postsynaptic membrane that are requirements for the channel gating. Coincidence detection by the NMDA receptor depends on a voltagedependent channel block by extracellular Mg2+. NMDA receptor-mediated excitotoxicity has been implicated in many important human brain pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer’s disease and Parkinson’s disease, depression, epilepsy, trauma and stroke to schizophrenia [14]
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