Inhibition of the Human Neuronal Sodium Channel Na1.9 by Arachidonyl-2-Chloroethylamide, An Analogue of Anandamide in a hNa1.9/rNa1.4 Chimera, An Experimental and in Silico Study.

Cannabinoids regulate analgesia, which has aroused much interest in identifying new pharmacological therapies in the management of refractory pain. Voltage-gated Na+ channels (Nas) play an important role in inflammatory and neuropathic pain. In particular, Na1.

Computational Molecular Characterization of the Interaction of Acetylcholine and the NMDA Receptor to Explain the Direct Glycine-Competitive Potentiation of NMDA-Mediated Neuronal Currents.

The activation of -methyl-d-aspartate receptor (NMDAR) is triggered by the closure of bilobed (D1 and D2) clamshell-like clefts upon binding glycine (Gly) and glutamate. There is evidence that cholinergic compounds modulate NMDAR-mediated currents via direct receptor-ligand interactions; however, molecular bases are unknown. Here, we first propose a mechanistic structure-based explanation for the observed ACh-induced submaximal potentiation of NMDA-elicited currents in striatal neurons by predicting competitive inhibition with Gly.

Chemometric Models of Differential Amino Acids at the Naα and Naβ Interface of Mammalian Sodium Channel Isoforms.

(1) Background: voltage-gated sodium channels (Nas) are integral membrane proteins that allow the sodium ion flux into the excitable cells and initiate the action potential. They comprise an α (Naα) subunit that forms the channel pore and are coupled to one or more auxiliary β (Naβ) subunits that modulate the gating to a variable extent. (2) Methods: after performing homology in silico modeling for all nine isoforms (Na1.

Mefloquine inhibits voltage dependent Na1.4 channel by overlapping the local anaesthetic binding site.

Mefloquine constitutes a multitarget antimalaric that inhibits cation currents. However, the effect and the binding site of this compound on Na channels is unknown. To address the mechanism of action of mefloquine, we employed two-electrode voltage clamp recordings on Xenopus laevis oocytes, site-directed mutagenesis of the rat Na channel, and a combined in silico approach using Molecular Dynamics and docking protocols.

Characterization of specific allosteric effects of the Na channel β1 subunit on the Na1.4 isoform.

The mechanism of inactivation of mammalian voltage-gated Na channels involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the β1 subunit. Naβ1 subunits constitute single-pass transmembrane proteins that form protein-protein associations with pore-forming α subunits to allosterically modulate the Na influx into the cell during the action potential of every excitable cell in vertebrates. Here, we explored the role of the intracellular IFM motif of rNa1.