發作性血色素尿症ニ就テ

The α4β2 nicotinic acetylcholine receptor (nAChR) is the most abundant subtype in the brain and exists in two functional stoichiometries: (α4)3(β2)2 and (α4)2(β2)3. A distinct feature of the (α4)3(β2)2 receptor is the biphasic activation response to the endogenous agonist acetylcholine, where it is activated with high potency and low efficacy when two α4-β2 binding sites are occupied and with low potency/high efficacy when a third α4-α4 binding site is occupied. Further, exogenous ligands can bind to the third α4-α4 binding site and potentiate the activation of the receptor by ACh that is bound at the two α4-β2 sites. We propose that perturbations of the recently described pre-activation step when a third binding site is occupied are a key driver of these distinct activation properties. To investigate this, we used a combination of simple linear kinetic models and voltage clamp electrophysiology to determine whether transitions into the pre-activated state were increased when three binding sites were occupied. We separated the binding at the two different sites with ligands selective for the α4-β2 site (Sazetidine-A and TC-2559) and the α4-α4 site (NS9283) and identified that when a third binding site was occupied, changes in the concentration-response curves were best explained by an increase in transitions into a pre-activated state. We propose that perturbations of transitions into a pre-activated state are essential to explain the activation properties of the (α4)3(β2)2 receptor by acetylcholine and other ligands. Considering the widespread clinical use of benzodiazepines, this discovery of a conserved mechanism that benzodiazepines and ACh potentiate receptor activation via a third binding site can be exploited to develop therapeutics with similar properties at other cys-loop receptors

Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4α2 nicotinic acetylcholine receptor: Antagonist binding site and mode of receptor inhibition revealed

Background: Methyllycaconitine is an antagonist at subtypes of the nicotinic acetylcholine receptor. Results: A reactive methyllycaconitine probe was covalently trapped by a cysteine introduced on the complementary face of the α4 subunit and only in the (α4)3(β2)2 nAChR stoichiometry. Conclusion: The α4-α4 interface on the α4β2 nAChR contains a methyllycaconitine binding site. Significance: Defining the molecular interactions of nAChR ligands at the α4-α interface may lead to superior therapeutics. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc

Modulating inhibitory ligand-gated ion channels

The glycine and γ-aminobutyric acid receptors (GlyR and GABAAR, respectively) are the major inhibitory neurotransmitter-gated receptors in the central nervous system of animals. Given the important role of these receptors in neuronal inhibition, they are prime targets of many therapeutic agents and are the object of intense studies aimed at correlating their structure and function. In this review, the structure and dynamics of these and other homologous members of the nicotinicoid superfamily are described. The modulatory actions of the major biological macromolecules that bind and allosterically affect these receptors are also discussed