| Ligand gated ion channels (LGIC's) are responsible for the conversion of neurochemical signals into electrical impulses. Such impulses are of either an excitatory or inhibitory form, depending on the permeability of the ion channel that has been activated. Importantly, the intrinsic functional properties (kinetics of activation, deactivation, desensitization, recovery from desensitization and agonist potency) of LGIC's are what determine the magnitude, duration and frequency of synaptic responses.; AMPA-type glutamate gated ion channels are responsible for the majority of excitatory synaptic transmission in mammals. The ubiquitous nature of these ion channels mandates their involvement in almost every neuronal pathway. Not surprisingly, the malfunction or inappropriate activation of these ion channels has been linked to numerous disease states including depression, schizophrenia, Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis (ALS).; AMPA receptors are tetrameric ion channels composed from four subunits (GluR1-4). All AMPA receptors subunits are subject to alternative mRNA splicing (flip/flop) and at least two forms of post-transcriptional modification (Q/R and R/G editing sites). These modifications result in the production of countless AMPA receptor subunits that display unique functional properties and pharmacological sensitivities. However, regardless of these variations all GluR1-4 subunits are capable of forming either homo- and heteroligomeric channels. Thus, association of different subunits also enhances functional diversity. Notably, although four GluR subunits coalesce into one functional tetramer, that tetramer contains four unique agonist-binding sites that are derived from each contributing subunit. Interestingly, the extent to which these sites are occupied by glutamate has been correlated with AMPAR single channel conductance levels (5, 15 and 23 pS).; AMPA receptor activation is promoted by glutamate binding. Lobes-1 (mostly S1) and -2 (mostly S2) of the glutamate binding pocket collapse around the agonist molecule and transfer the energy of binding across the dimer interface to cause rotational rearrangement of membrane spanning regions (TM1, 3, 4) and the reentrant (M2) pore loop region. These translational movements are believed to be necessary for opening of the ion channel pore. Indeed, destabilization of the dimmer interface has been proposed to be the primary mechanism underlying receptor desensitization. Thus, the dimer interface serves as a necessary connection between the ligand binding domain and the ion channel pore. The transitions "gating events" required for AMPA receptor activation and inactivation have garnered considerable attention because they represent pharmacological targets for the modulation of AMPA receptor and therefore glutamatergic synapse efficacy.; Channel gating specifically refers to the host of molecular transitions that are responsible for receptor fluctuations between closed-, open- and desensitized-channel states. Such events are exceedingly rapid (tens of microseconds) and are therefore difficult to measure. However, receptor gating events are commonly inferred or deduced from more accessible measures of receptor function: activation, deactivation, and desensitization. Although activation, deactivation and desensitization are empirical measures of current onset and decay, they can be used to assess changes in actual gating events that would otherwise be inaccessible to investigation: agonist association - kon, agonist dissociation - koff, channel opening - beta channel closing - alpha, or isomerization into - delta and out of - gamma the desensitized state.; Here AMPA receptor gating was explored and further defined by two alternative approaches. One approach relied on positive allosteric modulators and mutations that disrupt receptor-gating events. The actions of these modulators and mutations were exploited in order to determine the relationship that exists be... |
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