Ionotropic GABA and glutamate receptor mutations and human neurologic diseases

10.1124/mol.115.097998Molecular Pharmacology881203-21

Distinct roles of GRIN2A and GRIN2B variants in neurological conditions [version 1; peer review: 2 approved]

10.12688/f1000research.18949.1F1000Research8194

The first 50 years of molecular pharmacology

In this Perspective, former and current editors of Molecular Pharmacology, together with the guest editors for this 50th Anniversary Issue, provide a historical overview of the journal since its founding in 1965. The substantial impact that Molecular Pharmacology has had on the field of pharmacology as well as on biomedical science is discussed, as is the broad scope of the journal. The authors conclude that, true to the original goals for the journal, Molecular Pharmacology today remains an outstanding venue for work that provides a mechanistic understanding of drugs, molecular probes, and their biologic targets

Crystal structure and pharmacological characterization of a novel N methyl D aspartate NMDA receptor antagonist at the GluN1 glycine binding site

NMDA receptors are ligand gated ion channels that mediate excitatory neurotransmission in the brain. They are tetrameric complexes composed of glycine binding GluN1 and GluN3 subunits together with glutamate binding GluN2 subunits. Subunit selective antagonists that discriminate between the glycine sites of GluN1 and GluN3 subunits would be valuable pharmacological tools for studies on the function and physiological roles of NMDA receptor subtypes. In a virtual screening for antagonists that exploit differences in the orthosteric binding site of GluN1 and GluN3 subunits, we identified a novel glycine site antagonist, 1 thioxo 1,2 dihydro [1,2,4]triazolo[4,3 a]quinoxalin 4 5H one TK40 . Here, we show by Schild analysis that TK40 is a potent competitive antagonist with Kb values of 21 63 nm at the GluN1 glycine binding site of the four recombinant GluN1 N2A D receptors. In addition, TK40 displayed gt;100 fold selectivity for GluN1 N2 NMDA receptors over GluN3A and GluN3B containing NMDA receptors and no appreciable effects at AMPA receptors. Binding experiments on rat brain membranes and the purified GluN1 ligand binding domain using glycine site GluN1 radioligands further confirmed the competitive interaction and high potency. To delineate the binding mechanism, we have solved the crystal structure of the GluN1 ligand binding domain in complex with TK40 and show that TK40 binds to the orthosteric binding site of the GluN1 subunit with a binding mode that was also predicted by virtual screening. Furthermore, the structure reveals that the imino acetamido group of TK40 acts as an amp; 945; amino acid bioisostere, which could be of importance in bioisosteric replacement strategies for future ligand desig

Ionotropic Glutamate Like Receptor Delta 2 Binds D Serine and Glycine

The orphan glutamate like receptor GluR amp; 948;2 is predominantly expressed in Purkinje cells of the central nervous system. The classification of GluR amp; 948;2 to the ionotropic glutamate receptor family is based on sequence similarities, because GluR amp; 948;2 does not form functional homomeric glutamate gated ion channels in transfected cells. Studies in GluR amp; 948;2 amp; 8722; amp; 8722; knockout mice as well as in mice with naturally occurring mutations in the GluR amp; 948;2 gene have demonstrated an essential role of GluR amp; 948;2 in cerebellar long term depression, motor learning, motor coordination, and synaptogenesis. However, the lack of a known agonist has hampered investigations on the function of GluR amp; 948;2. In this study, the ligand binding core of GluR amp; 948;2 GluR amp; 948;2 S1S2 was found to bind neutral amino acids such as d serine and glycine, as demonstrated by isothermal titration calorimetry. Direct evidence for binding of d serine and structural rearrangements in the binding cleft of GluR amp; 948;2 S1S2 is provided by x ray structures of GluR amp; 948;2 S1S2 in its apo form and in complex with d serine. Functionally, d serine and glycine were shown to inactivate spontaneous ion channel conductance in GluR amp; 948;2 containing the lurcher mutation EC50 values, 182 and 507 amp; 956;M, respectively . These data demonstrate that the GluR amp; 948;2 ligand binding core is capable of binding ligands and that cleft closure of the ligand binding core can induce conformational changes that alter ion permeatio

Molecular determinants of proton-sensitive N-methyl-D-aspartate receptor gating

10.1124/mol.63.6.1212Molecular Pharmacology6361212-1222MOPM