Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT receptors.

Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT receptor (5-HTR), which features two properties: VTX acts differently on rodent and human 5-HTR, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HTR and an agonist-bound-like state of human 5-HTR, in line with the functional profile of the drug.

Conformational transitions of the serotonin 5-HT receptor.

The serotonin 5-HT receptor is a pentameric ligand-gated ion channel (pLGIC). It belongs to a large family of receptors that function as allosteric signal transducers across the plasma membrane; upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions that result in transient opening of a pore permeable to ions. 5-HT receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression.

Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit.

Zinc is abundant in the central nervous system and regulates pain, but the underlying mechanisms are unknown. In vitro studies have shown that extracellular zinc modulates a plethora of signaling membrane proteins, including NMDA receptors containing the NR2A subunit, which display exquisite zinc sensitivity. We created NR2A-H128S knock-in mice to investigate whether Zn2+-NR2A interaction influences pain control.

Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors.

N-Methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors endowed with unique pharmacological and functional properties. In particular, their high permeability to calcium ions confers on NMDARs a central role in triggering long term changes in synaptic strength. Under excitotoxic pathological conditions, such as those occurring during brain trauma, stroke, or Parkinson's or Huntington's diseases, calcium influx through NMDAR channels can also lead to neuronal injury.

Reactive derivatives for affinity labeling in the ifenprodil site of NMDA receptors.

To prepare thiol-reactive ifenprodil derivatives designed as potential probes for cysteine-substituted NR2B containing NMDA receptors, electrophilic centers were introduced in different areas of the ifenprodil structure. Intermediates and final compounds were evaluated by binding studies and by electrophysiology to determine the structural requirements for their selectivity. The reactive compounds were further tested for their stability and for their reactivity in model reactions; some were found suitable as structural probes to investigate the binding site and the docking mode of ifenprodil in the NR2B subunit.

Structural rearrangements of NR1/NR2A NMDA receptors during allosteric inhibition.

Ionotropic glutamate receptor (iGluR) subunits contain a large N-terminal domain (NTD) that precedes the agonist-binding domain (ABD) and participates in subunit oligomerization. In NMDA receptors (NMDARs), the NTDs of NR2A and NR2B subunits also form binding sites for the endogenous inhibitor Zn(2+) ion. Although these allosteric sites have been characterized in detail, the molecular mechanisms by which the NTDs communicate with the rest of the receptor to promote its inhibition remain unknown.

Synthesis and biological evaluation of 1-amino-2-phosphonomethylcyclopropanecarboxylic acids, new group III metabotropic glutamate receptor agonists.

Stereoisomers of 1-amino-2-phosphonomethylcyclopropanecarboxylic acid (APCPr), conformationally restricted analogues of L-AP4 (2-amino-4-phosphonobutyric acid), have been prepared and evaluated at recombinant group III metabotropic glutamate receptors. They activate these receptors over a broad range of potencies. The most potent isomer (1S,2R)-APCPr displays a similar pharmacological profile as that of L-AP4 (EC50 0.

A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family.

Ligand-gated ion channels (LGICs) mediate excitatory and inhibitory transmission in the nervous system. Among them, the pentameric or 'Cys-loop' receptors (pLGICs) compose a family that until recently was found in only eukaryotes. Yet a recent genome search identified putative homologues of these proteins in several bacterial species.

A startling role for synaptic zinc.

It has long been known that the synaptic vesicles of certain glutamatergic terminals, as well as some inhibitory terminals, are richly supplied with zinc ions, yet the functional role of this pool of zinc in synaptic transmission has remained elusive. In this issue of Neuron, Hirzel et al. provide direct in vivo evidence that endogenous zinc is required for proper functioning of neuronal circuitry in the brainstem and spinal cord.

NMDA receptor subunits: function and pharmacology.

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels widely expressed in the central nervous system that play key roles in excitatory synaptic transmission. Because of their involvement in numerous neurological disorders, NMDARs are also targets of therapeutic interest. NMDARs occur as multiple subtypes which differ in their subunit composition and in their biophysical and pharmacological properties.

The micromolar zinc-binding domain on the NMDA receptor subunit NR2B.

Eukaryotic ionotropic glutamate receptor subunits possess a large N-terminal domain (NTD) distinct from the neighboring agonist-binding domain. In NMDA receptors, the NTDs of NR2A and NR2B form modulatory domains binding allosteric inhibitors. Despite a high sequence homology, these two domains have been shown to bind two ligands of strikingly different chemical nature.

Identification of critical residues in the amino terminal domain of the human NR2B subunit involved in the RO 25-6981 binding pocket.

N-Methyl-d-aspartate (NMDA) receptors play key roles in both physiological processes, particularly synaptic plasticity, and in neuropathological states such as epilepsy and acute neurodegeneration. R-(R*,S*)-alpha-(4-Hydroxyphenyl)-beta-methyl-4-(phenyl-methyl)-1-piperidine propanol (RO 25-6981), is a high-affinity and selective blocker of NMDA receptors containing the NR2B subunit. Using site-directed mutagenesis, [3H]RO 25-6981 binding, Xenopus oocyte voltage-clamp recordings, and molecular modeling, we have identified several critical residues involved in the RO 25-6981 binding site within the N-terminal LIVBP-like domain of the human NR2B subunit.

Mapping the binding site of the neuroprotectant ifenprodil on NMDA receptors.

Ifenprodil is a noncompetitive antagonist of NMDA receptors highly selective for the NMDA receptor 2B (NR2B) subunit. It is widely used as a pharmacological tool to discriminate subpopulations of NMDA receptors, and derivatives are currently being developed as candidate neuroprotectants. Despite numerous studies on the mechanism of action of ifenprodil on NMDA receptors, the structural determinants responsible for the subunit selectivity have not been identified.