Electron cryo-microscopy structure of the canonical TRPC4 ion channel

Vinayagam, Deivanayagabarathy; Mager, Thomas; Apelbaum, Amir; Bothe, Arne; Merino, Felipe; Hofnagel, Oliver; Gatsogiannis, Christos; Raunser, Stefan

doi:10.7554/elife.36615

Cited by 86 publications

(64 citation statements)

References 83 publications

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“…Using these approaches, most recent studies discovered that in contrast to most other ligands, cholesterol binding is highly flexible and cholesterol dynamically explores its binding site, adopting multiple poses in a "cloud, " rather than occupying a single conformation (Gimpl, 2016;Genheden et al, 2017;Rouviere et al, 2017;Barbera et al, 2018). Recently electron cryo-microscopy structure of zebra fish TRPC4 (TRPC4 DR ) channel in its unliganded closed state, at an overall resolution of 3.6 Å was published (Vinayagam et al, 2018). The transmembrane S1-S6 helices structure revealed that in the pre-S1 elbow domain inside the membrane, a cavity is formed with helices S1 and S4, in which a density corresponding to a sterol is formed (Figure 1).…”

Section: Modulation Of Mammalian Trpc Channel Activity By Cholesterolmentioning

confidence: 99%

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Modulation of Transient Receptor Potential C Channel Activity by Cholesterol

et al. 2019

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Changes of cholesterol level in the plasma membrane of cells have been shown to modulate ion channel function. The proposed mechanisms underlying these modulations include association of cholesterol to a single binding site at a single channel conformation, association to a highly flexible cholesterol binding site adopting multiple poses, and perturbation of lipid rafts. These perturbations have been shown to induce reversible targeting of mammalian transient receptor potential C (TRPC) channels to the cholesterolrich membrane environment of lipid rafts. Thus, the observed inhibition of TRPC channels by methyl-β-cyclodextrin (MβCD), which induces cholesterol efflux from the plasma membrane, may result from disruption of lipid rafts. This perturbation was also shown to disrupt multimolecular signaling complexes containing TRPC channels. The Drosophila TRP and TRP-like (TRPL) channels belong to the TRPC channel subfamily. When the Drosophila TRPL channel was expressed in S2 or HEK293 cells and perfused with MβCD, the TRPL current was abolished in less than 100 s, fitting well the fast kinetic phase of cholesterol sequestration experiments in cells. It was thus suggested that the fast kinetics of TRPL channel suppression by MβCD arise from disruption of lipid rafts. Accordingly, lipid raft perturbation by cholesterol sequestration could give clues to the function of lipid environment in TRPC channel activity and its mechanism.

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Section: Modulation Of Mammalian Trpc Channel Activity By Cholesterolmentioning

confidence: 99%

“…The transmembrane S1-S6 helices structure revealed that in the pre-S1 elbow domain inside the membrane, a cavity is formed with helices S1 and S4, in which a density corresponding to a sterol is formed. (Reproduced from Vinayagam et al (2018) with permission from eLife.) application of Cav-1 scaffolding domain.…”

Section: Trpc3mentioning

confidence: 99%

Modulation of Transient Receptor Potential C Channel Activity by Cholesterol

et al. 2019

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“…Cryo-EM structures of mouse TRPC4:C4 (Duan et al, 2018), zebrafish TRPC4:C4 (Vinayagam et al, 2018), and mouse TRPC5:C5 (Duan et al, 2019) have recently been reported. However, the precise native stoichiometries of TRPC1/4/5 channels are largely unknown (Minard et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivative

Minard

Bauer

Chuntharpursat‐Bon

et al. 2019

British J Pharmacology

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Background and Purpose The TRPC1, TRPC4, and TRPC5 proteins form homotetrameric or heterotetrameric, calcium‐permeable cation channels that are involved in various disease states. Recent research has yielded specific and potent xanthine‐based TRPC1/4/5 inhibitors. Here, we investigated the possibility of xanthine‐based activators of these channels. Experimental Approach An analogue of the TRPC1/4/5 inhibitor Pico145, AM237, was synthesized and its activity was investigated using HEK cells overexpressing TRPC4, TRPC5, TRPC4–C1, TRPC5–C1, TRPC1:C4 or TRPC1:C5 channels, and in A498 cells expressing native TRPC1:C4 channels. TRPC1/4/5 channel activities were assayed by measuring intracellular concentration of Ca2+ ([Ca2+]i) and by patch‐clamp electrophysiology. Selectivity of AM237 was tested against TRPC3, TRPC6, TRPV4, or TRPM2 channels. Key Results AM237 potently activated TRPC5:C5 channels (EC50 15–20 nM in [Ca2+]i assay) and potentiated their activation by sphingosine‐1‐phosphate but suppressed activation evoked by (−)‐englerin A (EA). In patch‐clamp studies, AM237 activated TRPC5:C5 channels, with greater effect at positive voltages, but with lower efficacy than EA. Pico145 competitively inhibited AM237‐induced TRPC5:C5 activation. AM237 did not activate TRPC4:C4, TRPC4–C1, TRPC5–C1, TRPC1:C5, and TRPC1:C4 channels, or native TRPC1:C4 channels in A498 cells, but potently inhibited EA‐dependent activation of these channels with IC50 values ranging from 0.9 to 7 nM. AM237 (300 nM) did not activate or inhibit TRPC3, TRPC6, TRPV4, or TRPM2 channels. Conclusions and Implications This study suggests the possibility for selective activation of TRPC5 channels by xanthine derivatives and supports the general principle that xanthine‐based compounds can activate, potentiate, or inhibit these channels depending on subunit composition.

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“…Recently, the protein structure of TRPC3/4/5/6 have been resolved by cryo-EM with an atomic resolution [81,140,[169][170][171]. The detailed 3D structure offers a new way to evaluate potential residues that are critical for the gating and/or permeation of TRPCs.…”

Section: Discussionmentioning

confidence: 99%

Post-Translational Modification and Natural Mutation of TRPC Channels

Liu

Yao

Tsang

2020

Cells

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Transient Receptor Potential Canonical (TRPC) channels are homologues of Drosophila TRP channel first cloned in mammalian cells. TRPC family consists of seven members which are nonselective cation channels with a high Ca2+ permeability and are activated by a wide spectrum of stimuli. These channels are ubiquitously expressed in different tissues and organs in mammals and exert a variety of physiological functions. Post-translational modifications (PTMs) including phosphorylation, N-glycosylation, disulfide bond formation, ubiquitination, S-nitrosylation, S-glutathionylation, and acetylation play important roles in the modulation of channel gating, subcellular trafficking, protein-protein interaction, recycling, and protein architecture. PTMs also contribute to the polymodal activation of TRPCs and their subtle regulation in diverse physiological contexts and in pathological situations. Owing to their roles in the motor coordination and regulation of kidney podocyte structure, mutations of TRPCs have been implicated in diseases like cerebellar ataxia (moonwalker mice) and focal and segmental glomerulosclerosis (FSGS). The aim of this review is to comprehensively integrate all reported PTMs of TRPCs, to discuss their physiological/pathophysiological roles if available, and to summarize diseases linked to the natural mutations of TRPCs.

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Electron cryo-microscopy structure of the canonical TRPC4 ion channel

Cited by 86 publications

References 83 publications

Modulation of Transient Receptor Potential C Channel Activity by Cholesterol

Modulation of Transient Receptor Potential C Channel Activity by Cholesterol

Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivative

Post-Translational Modification and Natural Mutation of TRPC Channels

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