The coupling interface and pore domain codetermine the single-channel activity of the α7 nicotinic receptor

Yan, Hongxia; Pan, Na; Xue, Fenqin; Zheng, Yi; Li, Chaokun; Chang, Yongchang; Xu, Zhi‐Qing David; Yang, Hui; Zhang, Jianliang

doi:10.1016/j.neuropharm.2015.04.010

Cited by 10 publications

(8 citation statements)

References 37 publications

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“…The residue S346 is an essential molecular determinant of the α3GlyR conductance. Previous studies have shown that the conductance of pLGICs is determined primarily by the amino acid composition of the TM domains 4, [34][35][36] . Nevertheless, other studies have shown that the mutation of charged residues in the Figure 1.…”

Section: Resultsmentioning

confidence: 99%

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Moraga-Cid

Martín

Lara

et al. 2020

Sci Rep

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Glycine receptors (GlyRs) are anion-permeable pentameric ligand-gated ion channels (pLGICs). The GlyR activation is critical for the control of key neurophysiological functions, such as motor coordination, respiratory control, muscle tone and pain processing. The relevance of the GlyR function is further highlighted by the presence of abnormal glycinergic inhibition in many pathophysiological states, such as hyperekplexia, epilepsy, autism and chronic pain. In this context, previous studies have shown that the functional inhibition of GlyRs containing the α3 subunit is a pivotal mechanism of pain hypersensitivity. This pathway involves the activation of EP2 receptors and the subsequent PKAdependent phosphorylation of α3GlyRs within the intracellular domain (ICD), which decrease the GlyR-associated currents and enhance neuronal excitability. Despite the importance of this mechanism of glycinergic dis-inhibition associated with dysfunctional α3GlyRs, our current understanding of the molecular events involved is limited. Here, we report that the activation of PKA signaling pathway decreases the unitary conductance of α3GlyRs. We show in addition that the substitution of the PKAtargeted serine with a negatively charged residue within the ICD of α3GlyRs and of chimeric receptors combining bacterial GLic and α3GlyR was sufficient to generate receptors with reduced conductance. Thus, our findings reveal a potential biophysical mechanism of glycinergic dis-inhibition and suggest that post-translational modifications of the ICD, such as phosphorylation, may shape the conductance of other pLGICs. Glycine receptors (GlyRs) belong to the pentameric ligand-gated ion channel (pLGIC) family. GlyRs are anion-permeable channels, allowing the fast influx of chloride and the control of neuronal excitability. An individual GlyR subunit is composed by an extracellular domain (ECD), four transmembrane domains (TM1-4) and an intracellular domain between the TM3 and TM4 domains (ICD) 1-4. To date, a single β subunit and four α subunits (α1-4) has been described. The α subunits share a high degree of sequence identity (≈75%). Nevertheless, they exhibit important differences in their biophysical and pharmacological properties as well as in their distribution along the CNS 1,3,4. In the mammalian CNS, GlyR activity critically controls neurophysiological functions such as motor coordination, respiratory control, muscle tone, as well as pain processing 2,3,5-13. The importance of glycinergic inhibition was first recognized in studies using the GlyR antagonist strychnine 14,15. Later, genetic studies found that mutations in the GlyR α1 and β genes are linked to hyperekplexia in humans 16. More recent evidence has shown that specific GlyR subunits may play key roles in several diseases. For example, while the α1 subunit has been linked to tumorigenesis and alcohol intoxication 17,18 , mutations in the α2 subunit have been linked to autism 19. Alterations in the RNA processing of α3 subunits generates hyperactive receptors, which have been rela...

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Section: Resultsmentioning

confidence: 99%

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Moraga-Cid

Martín

Lara

et al. 2020

Sci Rep

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“…The α7-nAChR is a fast desensitizing receptor whose current response rapidly declines in the presence of saturating ACh concentrations due to channel closing 96 98 99 100 101 102 103 104 105 106 107 108 109 110 . Compared with the α7-nAChR, in the case of the chimeric α7-GluClβR studied here, the current declines much slower under saturating ACh concentration (e.g., Fig.…”

Section: Resultsmentioning

confidence: 99%

Trapping of ivermectin by a pentameric ligand-gated ion channel upon open-to-closed isomerization

Degani-Katzav

Klein

Har-Even

et al. 2017

Sci Rep

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Ivermectin (IVM) is a broad-spectrum anthelmintic drug used to treat human parasitic diseases like river blindness and lymphatic filariasis. By activating invertebrate pentameric glutamate-gated chloride channels (GluCl receptors; GluClRs), IVM induces sustained chloride influx and long-lasting membrane hyperpolarization that inhibit neural excitation in nematodes. Although IVM activates the C. elegans heteromeric GluClα/β receptor, it cannot activate a homomeric receptor composed of the C. elegans GluClβ subunits. To understand this incapability, we generated a homopentameric α7-GluClβ chimeric receptor that consists of an extracellular ligand-binding domain of an α7 nicotinic acetylcholine receptor known to be potentiated by IVM, and a chloride-selective channel domain assembled from GluClβ subunits. Application of IVM prior to acetylcholine inhibited the responses of the chimeric α7-GluClβR. Adding IVM to activated α7-GluClβRs, considerably accelerated the decline of ACh-elicited currents and stabilized the receptors in a non-conducting state. Determination of IVM association and dissociation rate constants and recovery experiments suggest that, following initial IVM binding to open α7-GluClβRs, the drug induces a conformational change and locks the ion channel in a closed state for a long duration. We further found that IVM also inhibits the activation by glutamate of a homomeric receptor assembled from the C. elegans full-length GluClβ subunits.

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“…Thus, a7 has a very low open probability. Single-channel openings exhibit a broad distribution of current amplitudes, probably owing to limited time resolution of the brief openings, with a maximum of ∼10 pA at -70 mV (Mike et al, 2000;Bouzat et al, 2008;Andersen et al, 2013;daCosta and Sine, 2013;Yan et al, 2015).…”

Section: A7 Channel Kineticsmentioning

confidence: 99%

“…2). The interface between the ECD and TMD, also referred to as the coupling region, is important for coupling agonist binding to channel opening (Bouzat et al, 2004;Lee and Sine, 2005;Castillo et al, 2006;Bartos et al, 2009), as well as for determining open channel lifetime and rate of desensitization (Bouzat et al, 2008;Yan et al, 2015) (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

2016

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The nicotinic acetylcholine receptor (nAChR) belongs to a superfamily of pentameric ligand-gated ion channels involved in many physiologic and pathologic processes. Among nAChRs, receptors comprising the a7 subunit are unique because of their high Ca 21 permeability and fast desensitization. nAChR agonists elicit a transient ion flux response that is further sustained by the release of calcium from intracellular sources. Owing to the dual ionotropic/metabotropic nature of a7 receptors, signaling pathways are activated. The a7 subunit is highly expressed in the nervous system, mostly in regions implicated in cognition and memory and has therefore attracted attention as a novel drug target. Additionally, its dysfunction is associated with several neuropsychiatric and neurologic disorders, such as schizophrenia and Alzheimer's disease. a7 is also expressed in non-neuronal cells, particularly immune cells, where it plays a role in immunity, inflammation, and neuroprotection. Thus, a7 potentiation has emerged as a therapeutic strategy for several neurologic and inflammatory disorders. With unique activation properties, the receptor is a sensitive drug target carrying different potential binding sites for chemical modulators, particularly agonists and positive allosteric modulators. Although macroscopic and singlechannel recordings have provided significant information about the underlying molecular mechanisms and binding sites of modulatory compounds, we know just the tip of the iceberg. Further concerted efforts are necessary to effectively exploit a7 as a drug target for each pathologic situation. In this article, we focus mainly on the molecular basis of activation and drug modulation of a7, key pillars for rational drug design.

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The coupling interface and pore domain codetermine the single-channel activity of the α7 nicotinic receptor

Cited by 10 publications

References 37 publications

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Modulation of glycine receptor single-channel conductance by intracellular phosphorylation

Trapping of ivermectin by a pentameric ligand-gated ion channel upon open-to-closed isomerization

Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

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