Abstract
Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function.
Highlights
Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes
Gating of amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors (AMPARs) and kainate receptors (KARs) does not require all four subunits to be bound to an agonist, allowing single-channel currents to show multiple conductance levels depending on LBD occupancy [106,107,108]
For the remainder of this section, we focus on AMPARs and KARs with Q
Summary
Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes. Activation refers to the transition of ion channels from closed to open states following application of agonist. Deactivation refers to the transition of channels from open to closed states following removal of agonist. A fourth gating mechanism that resembles desensitization but is not driven by agonist binding was referred to both as desensitization and inactivation [2,3,4], inactivation is a term typically used to describe a different mechanism employed by voltage-gated channels [5]. Channel gating requires conformational changes in or near the channel pore (i.e., the transmembrane ion conduction pathway), and channel blockers are known to interact differentially with channels in open, closed, inactivated, and desensitized states [3,7,8,9,10]. We discuss the interaction between channel block and channel gating of excitatory ligand-gated ion channels, with a focus on ionotropic glutamate receptors
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