An outline of desensitization in pentameric ligand-gated ion channel receptors

Keramidas, Angelo; Lynch, Joseph W.

doi:10.1007/s00018-012-1133-z

Cited by 34 publications

(34 citation statements)

References 105 publications

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“…The analysis of our chimeric constructs between GlyR␣1 and GLIC revealed differences in desensitization properties. In contrast, other ion channel properties such as channel block and ion selectivity are designated by regions outside of the ICD, e.g., the TM2-3 loop with interactions to pre-M1 [19]. Besides the large ICD, amino acid substitutions in the other intracellular TM1-2 loop identified in human patients suffering from the neuromotor disorder hyperekplexia have also been shown to drastically change desensitization properties of GlyR␣1 [20].…”

Section: Discussionmentioning

confidence: 92%

Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization

Langlhofer

Janzen

Meiselbach

et al. 2015

Neuroscience Letters

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Section: Discussionmentioning

confidence: 92%

Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization

Langlhofer

Janzen

Meiselbach

et al. 2015

Neuroscience Letters

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“…The diverging occupancy-activation relationship for the α7-5HT 3 A chimera demonstrates that the transmembrane domain or the interface between the transmembrane and extracellular domains that differs between α7 and α7-5HT 3 A (13), or an interplay with the ligand binding domain contribute to this relationship. It remains to be elucidated whether desensitization, which may contribute to α7 open-channel lifetime through a not yet fully known structural mechanism (10,(34)(35)(36), affects this relationship.…”

Section: Discussionmentioning

confidence: 99%

Stoichiometry for activation of neuronal α7 nicotinic receptors

Andersen

Corradi

Sine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

118

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Neuronal α7 nicotinic receptors elicit rapid cation influx in response to acetylcholine (ACh) or its hydrolysis product choline. They contribute to cognition, synaptic plasticity, and neuroprotection and have been implicated in neurodegenerative and neuropsychiatric disorders. α7, however, often localizes distal to sites of nerve-released ACh and binds ACh with low affinity, and thus elicits its biological response with low agonist occupancy. To assess the function of α7 when ACh occupies fewer than five of its identical binding sites, we measured the open-channel lifetime of individual receptors in which four of the five ACh binding sites were disabled. To improve the time resolution of the inherently brief α7 channel openings, background mutations or a potentiator was used to increase open duration. We find that, in receptors with only one intact binding site, the open-channel lifetime is indistinguishable from receptors with five intact binding sites, counter to expectations from prototypical neurotransmitter-gated ion channels where the open-channel lifetime increases with the number of binding sites occupied by agonist. Replacing the membrane-embedded domain of α7 by that of the related 5-HT 3 A receptor increases the number of sites that need to be occupied to achieve the maximal open-channel lifetime, thus revealing a unique interdependence between the detector and actuator domains of these receptors. The distinctive ability of a single occupancy to elicit a full biological response adapts α7 to volume transmission, a prevalent mechanism of ACh-mediated signaling in the nervous system and nonneuronal cells.Cys-loop receptors | α7 nicotinic receptor | patch-clamp | agonist binding site | channel gating

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“…A two-gate model with distinct activation and desensitization gates has been suggested for cysteine loop ligand-gated ion channels (Auerbach and Akk, 1998;Keramidas and Lynch, 2013). One possibility for P2X receptors is that the agonist-induced movement of the TMs triggers a conformational change in the intracellular regions of the receptor that blocks ionic permeation through the channel.…”

Section: Discussionmentioning

confidence: 99%

Kinetics of Conformational Changes Revealed by Voltage-Clamp Fluorometry Give Insight to Desensitization at ATP-Gated Human P2X1 Receptors

Fryatt

Evans

2014

Mol Pharmacol

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ATP acts as an extracellular signaling molecule at cell-surface P2X receptors, mediating a variety of important physiologic and pathophysiologic roles. Homomeric P2X1 receptors open on binding ATP and then transition to an ATP-bound closed, desensitized state that requires an agonist-free washout period to recover. Voltage-clamp fluorometry was used to record ion channel activity and conformational changes simultaneously at defined positions in the extracellular loop of the human P2X1 receptor during not only agonist binding and desensitization but also during recovery. ATP evoked distinct conformational changes adjacent to the agonist binding pocket in response to channel activation and desensitization. The speed of recovery of the conformational change on agonist washout was statedependent, with a faster time constant from the open (5 seconds) compared with the desensitized (75 seconds) form of the channel. The ability of ATP to evoke channel activity on washout after desensitization was not dependent on the degree of conformational rearrangement in the extracellular loop, and desensitization was faster from the partially recovered state. An intracellular mutation in the carboxyl terminus that slowed recovery of P2X1 receptor currents (7-fold less recovery at 30 seconds) had no effect on the time course of the extracellular conformational rearrangements. This study highlights that the intracellular portion of the receptor can regulate recovery and shows for the first time that this is by a mechanism independent of changes in the extracellular domain, suggesting the existence of a distinct desensitization gate in this novel class of ligand gated ion channels.

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An outline of desensitization in pentameric ligand-gated ion channel receptors

Cited by 34 publications

References 105 publications

Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization

Length of the TM3-4 loop of the glycine receptor modulates receptor desensitization

Stoichiometry for activation of neuronal α7 nicotinic receptors

Kinetics of Conformational Changes Revealed by Voltage-Clamp Fluorometry Give Insight to Desensitization at ATP-Gated Human P2X1 Receptors

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