N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca²(+)-permeable cation channels which are blocked by extracellular Mg²(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.

N-methyl D-aspartate receptors (NMDAR) play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D) and two GluN3 (A–B) subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD) and ligand binding domain (LBD), transmembrane domain (TMD) and an intracellular C-terminal domain (CTD). Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate) potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A) than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.

Individuals suffering from Type 2 diabetes develop prediabetes before progression of diabetes. In case of prediabetes people, the blood glucose levels are higher than normal but not sufficient to be diagnosed as diabetes. On the basis of existing reports on Sesame extract, SesaVita TM which is an herbal food supplement containing Sesame seeds (Sesamum indicum L.) extract may provide an option for management of prediabetes. The objective of this study was to determine the beneficial effects of SesaVita TM in prediabetes and mild to moderate hyperlipidemia subjects. This randomized, placebo-controlled, double-blind study comprised of 13 female and 07 male patients with prediabetes and mild to moderate hyperlipidemia, aged between 18 and 65 years. Twenty subjects were randomized to receive SesaVita TM (500 mg/day) or placebo along with therapeutic lifestyle changes for 6 weeks. The primary outcome was the measure of efficacy in terms of change in serum lipid profile and glycaemic levels on week 3 and 6. Secondary outcome measures include safety and tolerability evaluated by physical examination and clinical laboratory evaluations. Improvements in lipid profile and glycaemic levels were observed in SesaVita TM treated group when compared with placebo and baseline. A statistical significant reduction was observed in low density lipoprotein cholesterol (LDL-C), total cholesterol (TC), oral glucose tolerance test (OGTT) and fasting blood sugar (FBS) levels during week 3 and 6 when treated with SesaVita TM extract. No adverse events occurred and all safety parameters were within normal ranges during the study. This study revealed that the treatment with SesaVita TM was safe and well tolerated; may be beneficial in the management of prediabetes and mild-to-moderate hyperlipidemia.