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Certain types of nonpsychoactive cannabinoids can potentiate glycine receptors (GlyRs), an important target for nociceptive regulation at the spinal level. However, little is known about the potential and mechanism of glycinergic cannabinoids for chronic pain treatment. We report that systemic and intrathecal administration of cannabidiol (CBD), a major(More)
ELIC, the pentameric ligand-gated ion channel from Erwinia chrysanthemi, is a prototype for Cys-loop receptors. Here we show that acetylcholine is a competitive antagonist for ELIC. We determine the acetylcholine-ELIC cocrystal structure to a 2.9-Å resolution and find that acetylcholine binding to an aromatic cage at the subunit interface induces a(More)
Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but a structural understanding of anesthetic action on pLGICs remains elusive. GLIC, a prokaryotic pLGIC, can be inhibited by anesthetics, including ketamine. The ketamine concentration leading to half-maximal inhibition of GLIC (58 μM) is comparable to that on neuronal(More)
The neuronal alpha4beta2 nicotinic acetylcholine receptor (nAChR) is a potential molecular target for general anesthetics. It is unclear, however, whether anesthetic action produces the same effect on the open and closed channels. Computations parallel to our previous open channel study (J. Phys. Chem. B 2009, 113, 12581) were performed on the(More)
The neuronal alpha4beta2 nicotinic acetylcholine receptor (nAChR) is a target for general anesthetics. Currently available experimental structural information is inadequate to understand where anesthetics bind and how they modulate the receptor motions essential to function. Using our published open-channel structure model of alpha4beta2 nAChR, we(More)
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel cause cystic fibrosis. The delta F508 mutation produces defects in channel gating and cellular processing, whereas the G551D mutation produces primarily a gating defect. To identify correctors of gating, 50,000 diverse small molecules were screened at 2.5 microM(More)
Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as targets for general anesthetics, but the functional responses to anesthetic modulation vary considerably among different subtypes of nAChRs. Inhaled general anesthetics, such as halothane, could effectively inhibit the channel activity of the alpha4beta2 nAChR but not the homologous(More)
The anesthetic propofol inhibits the currents of the homopentameric ligand-gated ion channel GLIC, yet the crystal structure of GLIC with five propofol molecules bound symmetrically shows an open-channel conformation. To address this dilemma and determine if the symmetry of propofol binding sites affects the channel conformational transition, we performed a(More)
Pentameric ligand-gated ion channels are targets of general anesthetics. Although the search for discrete anesthetic binding sites has achieved some degree of success, little is known regarding how anesthetics work after the events of binding. Using the crystal structures of the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC),(More)
Water is an essential component for many biological processes. Pauling proposed that water might play a critical role in general anesthesia by forming water clathrates around anesthetic molecules. To examine potential involvement of water in general anesthesia, we analyzed water within alpha4beta2 nAChR, a putative protein target hypersensitive to volatile(More)