title: The desensitization gate of inhibitory Cys-loop receptors.
abstract: Cys-loop neurotransmitter-gated ion channels are vital for communication throughout the nervous system. Following activation, these receptors enter into a desensitized state in which the ion channel shuts even though the neurotransmitter molecules remain bound. To date, the molecular determinants underlying this most fundamental property of Cys-loop receptors have remained elusive. Here we present a generic mechanism for the desensitization of Cys-loop GABAA (GABAARs) and glycine receptors (GlyRs), which both mediate fast inhibitory synaptic transmission. Desensitization is regulated by interactions between the second and third transmembrane segments, which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker picrotoxin prevented desensitization, consistent with its deep channel-binding site overlapping a physical desensitization gate.
authors.affiliation: Department of Neuroscience, Physiology &Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Gielen
authors.affiliation: Department of Neuroscience, Physiology &Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Department of Neuroscience, Physiology &Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D009865:Oocytes; D011487:Protein Conformation; D021122:Protein Subunits; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins; D014982:Xenopus laevis
chemical_list: D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors; D021122:Protein Subunits; D018009:Receptors, Glycine; D011994:Recombinant Proteins