From betel nuts to Cobenfy: how an ancient recreational drug gave rise to a new class of schizophrenia medications.

The term "betel" most accurately refers to the betel pepper (). Confusingly, this term is also frequently used to refer to a street drug that often-but not always-includes the betel leaf as a constituent. This linguistic misdirection only intensifies with terms such as "betel nut," which, in common usage, may refer to this same composite street drug or to a single isolated constituent of that street drug: the nut of the areca palm (), which is otherwise wholly unrelated to the betel pepper.

Two gates mediate NMDA receptor activity and are under subunit-specific regulation.

Kinetics of NMDA receptor (NMDAR) ion channel opening and closing contribute to their unique role in synaptic signaling. Agonist binding generates free energy to open a canonical gate at the M3 helix bundle crossing. Single channel activity is characterized by clusters, or periods of rapid opening and closing, that are separated by long silent periods.

NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity.

NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate fast excitatory synaptic transmission in the nervous system. Applying glutamate to outside-out patches containing a single NMDAR, we find that agonist-bound receptors transition to the open state via two conformations, an "unconstrained pre-active" state that contributes to fast synaptic events and a "constrained pre-active" state that does not. To define how glutamate drives these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for GluN1 and GluN2A.

From bedside-to-bench: What disease-associated variants are teaching us about the NMDA receptor.

NMDA receptors (NMDARs) are glutamate-gated ion channels that contribute to nearly all brain processes. Not surprisingly then, genetic variations in the genes encoding NMDAR subunits can be associated with neurodevelopmental, neurological and psychiatric disorders. These disease-associated variants (DAVs) present challenges, such as defining how DAV-induced alterations in receptor function contribute to disease progression and how to treat the affected individual clinically.

De novo GRIN variants in NMDA receptor M2 channel pore-forming loop are associated with neurological diseases.

N-methyl-D-aspartate receptors (NMDARs) mediate slow excitatory postsynaptic transmission in the central nervous system, thereby exerting a critical role in neuronal development and brain function. Rare genetic variants in the GRIN genes encoding NMDAR subunits segregated with neurological disorders. Here, we summarize the clinical presentations for 18 patients harboring 12 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M2 re-entrant loop, a region that lines the pore and is intolerant to missense variation.

A conserved glycine harboring disease-associated mutations permits NMDA receptor slow deactivation and high Ca permeability.

A variety of de novo and inherited missense mutations associated with neurological disorders are found in the NMDA receptor M4 transmembrane helices, which are peripheral to the pore domain in eukaryotic ionotropic glutamate receptors. Subsets of these mutations affect receptor gating with dramatic effects, including in one instance halting it, occurring at a conserved glycine near the extracellular end of M4. Functional experiments and molecular dynamic simulations of constructs with and without substitutions at this glycine indicate that it acts as a hinge, permitting the intracellular portion of the ion channel to laterally expand.

A Swiss army knife for targeting receptors.

A compound can change the activity of NMDA receptors in some regions of a synapse without affecting those in other regions.

Divergent roles of a peripheral transmembrane segment in AMPA and NMDA receptors.

Ionotropic glutamate receptors (iGluRs), including AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subtypes, are ligand-gated ion channels that mediate signaling at the majority of excitatory synapses in the nervous system. The iGluR pore domain is structurally and evolutionarily related to an inverted two-transmembrane K channel. Peripheral to the pore domain in eukaryotic iGluRs is an additional transmembrane helix, the M4 segment, which interacts with the pore domain of a neighboring subunit.