Elephants in the Dark: Insights and Incongruities in Pentameric Ligand-gated Ion Channel Models

Howard, Rebecca J.

doi:10.1016/j.jmb.2021.167128

Cited by 31 publications

(29 citation statements)

References 173 publications

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“…Together, the combined simulations and electrophysiology data demonstrate that the chloride flux within the ECD of GlyR-α1 is controlled by lateral fenestrations. This discovery provides an unanticipated pathway for chloride permeation that challenges the apical translocation model commonly accepted in pLGICs ( 30 – 32 ).…”

Section: Discussionmentioning

confidence: 99%

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

et al. 2022

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Glycine receptors (GlyRs) are ligand-gated ion channels mediating signal transduction at chemical synapses. Since the early patch-clamp electrophysiology studies, the details of the ion permeation mechanism have remained elusive. Here, we combine molecular dynamics simulations of a zebrafish GlyR-α1 model devoid of the intracellular domain with mutagenesis and single-channel electrophysiology of the full-length human GlyR-α1. We show that lateral fenestrations between subunits in the extracellular domain provide the main translocation pathway for chloride ions to enter/exit a central water-filled vestibule at the entrance of the transmembrane channel. In addition, we provide evidence that these fenestrations are at the origin of current rectification in known anomalous mutants and design de novo two inward-rectifying channels by introducing mutations within them. These results demonstrate the central role of lateral fenestrations on synaptic neurotransmission.

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Section: Discussionmentioning

confidence: 99%

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

et al. 2022

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“…Among Cys-loop receptors, strychnine-sensitive GlyR, the major inhibitory ionotropic receptor in the brainstem and spinal cord, has become by far the better characterized ( Howard, 2021 ): there are over 40 structures deposited in the Protein Data Bank, mostly in open, closed and desensitized-like states ( Du et al, 2015 ; Huang et al, 2015 , 2017b , 2017a ; Kumar et al, 2020 ; Yu J. et al, 2021 , Yu et al, 2021 H. ); a few are trapped in a super-open states, whose physiological significance has been questioned, specially by MD ( Cerdan et al, 2018 ; Cerdan and Cecchini, 2020 ; Dämgen and Biggin, 2020 ; Dämgen et al, 2020 ). Apart from these rich structural data, GlyR stands out among the eukaryotic PLGICs due to its role in neurological diseases and particularly in a rare Mendelian condition known as hyperekplexia (HPX) or “startle disease” ( Lynch et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations

Mhashal

Yoluk

Orellana

2022

Front. Mol. Biosci.

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Pentameric ligand-gated ion channels (PLGICs) are a family of proteins that convert chemical signals into ion fluxes through cellular membranes. Their structures are highly conserved across all kingdoms from bacteria to eukaryotes. Beyond their classical roles in neurotransmission and neurological disorders, PLGICs have been recently related to cell proliferation and cancer. Here, we focus on the best characterized eukaryotic channel, the glycine receptor (GlyR), to investigate its mutational patterns in genomic-wide tumor screens and compare them with mutations linked to hyperekplexia (HPX), a Mendelian neuromotor disease that disrupts glycinergic currents. Our analysis highlights that cancer mutations significantly accumulate across TM1 and TM2, partially overlapping with HPX changes. Based on 3D-clustering, conservation, and phenotypic data, we select three mutations near the pore, expected to impact GlyR conformation, for further study by molecular dynamics (MD). Using principal components from experimental GlyR ensembles as framework, we explore the motions involved in transitions from the human closed and desensitized structures and how they are perturbed by mutations. Our MD simulations show that WT GlyR spontaneously explores opening and re-sensitization transitions that are significantly impaired by mutations, resulting in receptors with altered permeability and desensitization properties in agreement with HPX functional data.

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“…For many years, the family of nicotinic acetylcholine receptors (nAChRs) has been the focus of researchers’ interest as a vital target for the critical neurotransmitter acetylcholine (ACh), novel drugs (e.g., myorelaxants, analgesics, and neuroprotective agents) and natural toxins from bacteria, algae, plants, and animals [ 1 , 2 , 3 ]. The identification of nAChRs as the first neurotransmitter receptors has major practical consequences from the perspective of protein receptors targeting for therapeutic intervention and conception of allosteric modulation, including further development of allosteric pharmacological agents [ 4 , 5 ]. nAChRs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels.…”

Section: Introductionmentioning

confidence: 99%

“…nAChRs belong to the Cys-loop superfamily of pentameric ligand-gated ion channels. In mammals 16 nAChR subunits (α1–10, β1–4, γ, δ, and ε) form non-muscle receptors: homo-pentamers of α7, α8, and α9, hetero-pentamers of α2–α6 combined with β2–β4, or α7 with β2, and α9 with α10 subunits, and in muscles hetero-pentameric receptors composed of two α1, one β1 and δ, plus a fetal subunit γ further replaced by adult ε subunit [ 3 , 4 ]. nAChRs provide fast excitatory neurotransmission or neuromuscular transmission in both central and peripheral nervous systems and play pivotal roles in the etiology of neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

Nicotinic Acetylcholine Receptors Are Novel Targets of APETx-like Toxins from the Sea Anemone Heteractis magnifica

Kalina

Kasheverov

Koshelev

et al. 2022

Toxins

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The nicotinic acetylcholine receptors (nAChRs) are prototypical ligand-gated ion channels, provide cholinergic signaling, and are modulated by various venom toxins and drugs in addition to neurotransmitters. Here, four APETx-like toxins, including two new toxins, named Hmg 1b-2 Metox and Hmg 1b-5, were isolated from the sea anemone Heteractis magnifica and characterized as novel nAChR ligands and acid-sensing ion channel (ASIC) modulators. All peptides competed with radiolabeled α-bungarotoxin for binding to Torpedo californica muscle-type and human α7 nAChRs. Hmg 1b-2 potentiated acetylcholine-elicited current in human α7 receptors expressed in Xenopus laevis oocytes. Moreover, the multigene family coding APETx-like peptides library from H. magnifica was described and in silico surface electrostatic potentials of novel peptides were analyzed. To explain the 100% identity of some peptide isoforms between H. magnifica and H. crispa, 18S rRNA, COI, and ITS analysis were performed. It has been shown that the sea anemones previously identified by morphology as H. crispa belong to the species H. magnifica.

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Elephants in the Dark: Insights and Incongruities in Pentameric Ligand-gated Ion Channel Models

Cited by 31 publications

References 173 publications

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway

Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations

Nicotinic Acetylcholine Receptors Are Novel Targets of APETx-like Toxins from the Sea Anemone Heteractis magnifica

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