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The structures of AMPA receptors in complex with auxiliary proteins are resolved by cryo-electron microscopy, and reveal conformational and permeation pathway changes that are associated with activation and desensitization of ionotropic glutamate receptors.

CNS toxicity was unexpectedly observed for anti-miR-17 RGLS4326 in nonclinical studies. Here, authors identify AMPA receptor inhibition as the likely culprit. Replacement of 3’-terminus guanine to adenine leads to discovery of farabursen (RGLS8429) that is devoid of CNS toxicity.

TRP channel TRPV6 is a regulator of Ca2+ homeostasis. Here, authors decipher the mechanism of TRPV6 inhibition by intracellular Mg2+ ions that bind to four sites around the intracellular pore entrance and lock the channel in the closed state.

Gangwar et al. present cryo-electron microscopy structures of GluK2 kainate receptors with auxiliary subunit Neto2 and reveal the basis of receptor activation.

The cryo-electron microscopy structure of the calcium channel TRPV6 in its open and closed states demonstrates a novel gating mechanism involving an alanine hinge.

Kainate receptors (KARs) contribute to excitatory neurotransmission, neuronal plasticity and neurological disorders. Here, Gangwar et al. present KAR structures in complex with channel blockers NpTx8, PhTx74, KukoA, and spermine, which become trapped inside the channel upon its closure.

Structures of the kainate receptor GluK2 with and without concanavilin A and BPAM344 show how these ligands modulate channel activity and reveal the molecular basis of kainate receptor gating.

TRPV3 mediates cutaneous sensations such as itch and pain. Here authors present the cryo-EM structure of TRPV3 bound with local anesthetic which binds the channel in membrane portals that connect the membrane environment to the channel pore.

Gangwar et al. describe the cumulative effect of the potentiating CNIH2 and inhibitory γ5 auxiliary subunits on GluA2 AMPA receptor activation and desensitization gating, polyamine block and noncompetitive inhibition by antiepileptic drug perampanel.

The authors report the structure of human oncochannel TRPV6 in complex with the plant derived phytoestrogen genistein. The structure provides insights into genistein binding in the channel pore, and how it acts as blocker and gating modifier, suggesting a mechanism of inhibition that can be explored for the structure-based drug design.

Small molecules targeting transient receptor potential (TRP) channels might be used to control pain. Here, Neuberger et al. report cryo-EM structures of human TRPV1 in the absence of added ligands or in the presence of the TRPV1-specific antagonist SB-366791, providing insights for the design of new promising analgesics.

Nadezhdin et al. present structures of human TRPV4 in complex with the GTPase RhoA, in the apo, agonist 4α-PDD and antagonist HC-067047 bound states, uncovering the mechanisms of channel activation, inhibition and disease-causing mutations.

Neuberger et al. report the structure of human channel TRPV6 in complex with a cannabinoid inhibitor tetrahydrocannabivarin (THCV) and explore the pathway taken by the drug to reach binding sites in the portals that connect the membrane environment to the central cavity of the ion channel pore.

Authors present the structural mechanisms of TRPM7 spontaneous and agonist-induced opening and inhibition by potent and selective antagonists.

Cryo-EM structures of the heat-activated TRP channel TRPV3 in lipid nanodiscs at different temperatures reveal a conformational wave involved in the gating process.

Structural and functional characterization of the full-length TRPV1 channel from the thirteen-lined ground squirrel reveal the architecture of the extracellular cap domain and the intracellular C-terminus, and suggest a role of the cap domain in TRPV1 conductance and ion selectivity.

Transient receptor potential (TRP) channels are ubiquitous occurring cation-selective sensory ion channels that respond to various stimuli. Here the authors characterize crTRP1 from the alga Chlamydomonas reinhardtii, present its 3.5 Å cryo-EM structure and show that crTRP1 opens in response to increased temperature and is positively regulated by the membrane lipid PIP₂.

Cryo-EM structures of AMPA receptor with the subunit γ2 in non-desensitizing conditions at low glutamate concentrations disprove the one-to-one link between the number of glutamate-bound subunits and ionotropic glutamate receptor conductance.

The cryo-electron microscopy structures of the mouse TRPV3 channel, in the closed apo and agonist-bound open conformations, provide insights into the mechanism of activation.

TRPV6 is a calcium-selective ion channel that is involved in numerous calcium-dependent physiological processes and it is of interest as a potential drug target. Here, the authors present the cryo-EM structures of human TRPV6 with the bound inhibitors ruthenium red and the antifungal drug econazole and discuss their inhibition mechanisms.

The X-ray crystal structure of rat transient receptor potential channel TRPV6 at 3.25 Å resolution is reported, providing new insights into its assembly and calcium-selective permeation.

The transient receptor potential channel TRPV6 mediates calcium uptake in epithelia and its expression is increased in several cancer types. Here, authors present structures of TRPV6 bound to 2-APB, a TRPV6 inhibitor, and show that 2-APB induces TRPV6 channel closure by modulating protein–lipid interactions.

The majority of excitatory neurotransmission in the central nervous system is mediated by ionotropic glutamate receptors, which function by opening a transmembrane ion channel upon binding of glutamate. However, despite this crucial role in neurobiology, the architecture and atomic structure of an intact isotropic glutamate receptor are unknown. The X-ray crystal structure of the rat GluA2 receptor in complex with a competitive antagonist is now reported and analysed.

Cryo-EM structures of mouse TRPV3 in open, closed and intermediate states, obtained by incubation of the protein samples at different temperatures immediately prior to freezing, offer insight into conformational changes induced by heat in TRPV3.

Ion channels are known to be important actors in cellular signaling, and their functions correlate to their conformational states, however, detailed function–conformation relationships remain underexplored. Here, the authors use a molecular modeling-based approach to assess water and ion conductivity along with pore hydrophobicity and residue packing to characterize the ion channel structural intermediates, revealing three major states of vanilloid-subfamily transient receptor potential channels.