Structure of the Cardiac Sodium Channel

Jiang, Dequan; Shi, Hui; Tonggu, Lige; El-Din, Tamer M. Gamal; Lenaeus, Michael J.; Zhao, Yan; Yoshioka, Craig; Zheng, Ning; Catterall, William A.

doi:10.1016/j.cell.2019.11.041

Cited by 264 publications

(500 citation statements)

References 96 publications

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“…During this manuscript preparation, cryo-EM structures of a rat Nav1.5 variant that contains truncations in the I-II linker, the II-III linker, and the Cterminus was reported in complex with TTX and flecainide, a class Ic antiarrhythmic drug (34). There are only two overlapping points between the published paper and our present study, the molecular basis for TTX-resistance and the lack of β1 association.…”

Section: Discussionmentioning

confidence: 53%

Structural basis for pore blockade of the human cardiac sodium channel Na_v1.5 by tetrodotoxin and quinidine

Jin

Huang

et al. 2019

Preprint

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Among the nine subtypes of human voltage-gated Na + (Na v ) channels, tetrodotoxin (TTX)-resistant Na v 1.5 is the primary one in heart. More than 400 point mutations have been identified in Na v 1.5 that are associated with cardiac disorders exemplified by type 3 long QT syndrome and Brugada syndrome, making Na v 1.5 a common target for class I antiarrythmic drugs. Here we present the cryo-EM structures of Na v 1.5 bound to quinidine and TTX with resolutions at 3.2 Å and 3.3 Å, respectively, for the pore domain. The structures allow mapping of 278 disease-related mutations in the resolved region, establishing the framework for mechanistic investigation of these pathogenic mutations. Quinidine is positioned right below the selectivity filter and coordinated by residues from repeats I, III, and IV. Pore blockade is achieved through both direct obstruction of the ion permeation path and induced rotation of a Tyr residue that leads to intracellular gate closure. Structural comparison of Na v 1.5 with our previously reported Na v 1.2/1.4/1.7 reveals the molecular determinant for the different susceptibility to TTX by TTX-resistant and -sensitive Na v subtypes, and highlights the functional significance of the underexplored and least conserved extracellular loops.

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Section: Discussionmentioning

confidence: 53%

Structural basis for pore blockade of the human cardiac sodium channel Na_v1.5 by tetrodotoxin and quinidine

Jin

Huang

et al. 2019

Preprint

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“…NavMs and hNav1.1 exhibit similar ion flux and conductance properties, and as well as very similar binding affinities for a wide range of sodium channel-specific drugs (Bagneris et al, 2014). Structure/function/drug-binding studies using some of the other prokaryotic sodium channels have also showed their comparability to hNavs for drug binding (Payandeh et al, 2011;Jiang et al, 2019), and they too have been used for drug discovery projects (Martin & Corry, 2014;Ouyang et al, 2007), although their structures tend to be of lower resolution than those of NavMs. Much of the focus of this study has been on comparisons of NavMs with hNav1.2 and hNav1.1, as these are the sodium channels primarily found in human central nervous system tissues.…”

Section: Resultsmentioning

confidence: 99%

Cannabidiol Interactions with Voltage-Gated Sodium Channels

Sait

Sula

Hollingworth

et al. 2020

Preprint

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Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, showing CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies illuminate why the closely-related psychoactive compound THC may not bind to these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD with sodium channels.Introduction:

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“…Structural studies lately confirmed that pore opening provides a cytoplasmic entryway for tetrabutylammonium and “ball peptide” to gain access to central cavity sites below the selectivity filter and inner pore sites, ultimately leading to blockage of ion permeation (Zhou et al, 2001a). Moreover, Br-verapamil and flecainide, two drugs widely used for treating arrhythmias, respectively reach an analogous site in Ca v Ab and Nav1.5 via open pore and occlude the ion-conduction pathway (Tang et al, 2016; Jiang et al, 2019).…”

Section: The “Resolution Revolution” Led To Breakthrough In Trpv1 Structural Biologymentioning

confidence: 99%

Structural mechanisms of transient receptor potential ion channels

Cao

2020

Journal of General Physiology

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Transient receptor potential (TRP) ion channels are evolutionarily ancient sensory proteins that detect and integrate a wide range of physical and chemical stimuli. TRP channels are fundamental for numerous biological processes and are therefore associated with a multitude of inherited and acquired human disorders. In contrast to many other major ion channel families, high-resolution structures of TRP channels were not available before 2013. Remarkably, however, the subsequent “resolution revolution” in cryo-EM has led to an explosion of TRP structures in the last few years. These structures have confirmed that TRP channels assemble as tetramers and resemble voltage-gated ion channels in their overall architecture. But beyond the relatively conserved transmembrane core embedded within the lipid bilayer, each TRP subtype appears to be endowed with a unique set of soluble domains that may confer diverse regulatory mechanisms. Importantly, TRP channel structures have revealed sites and mechanisms of action of numerous synthetic and natural compounds, as well as those for endogenous ligands such as lipids, Ca2+, and calmodulin. Here, I discuss these recent findings with a particular focus on the conserved transmembrane region and how these structures may help to rationally target this important class of ion channels for the treatment of numerous human conditions.

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Structure of the Cardiac Sodium Channel

Cited by 264 publications

References 96 publications

Structural basis for pore blockade of the human cardiac sodium channel Na_v1.5 by tetrodotoxin and quinidine

Structural basis for pore blockade of the human cardiac sodium channel Na_v1.5 by tetrodotoxin and quinidine

Cannabidiol Interactions with Voltage-Gated Sodium Channels

Structural mechanisms of transient receptor potential ion channels

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Structure of the Cardiac Sodium Channel

Cited by 264 publications

References 96 publications

Structural basis for pore blockade of the human cardiac sodium channel Nav1.5 by tetrodotoxin and quinidine

Structural basis for pore blockade of the human cardiac sodium channel Nav1.5 by tetrodotoxin and quinidine

Cannabidiol Interactions with Voltage-Gated Sodium Channels

Structural mechanisms of transient receptor potential ion channels

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Product

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Structural basis for pore blockade of the human cardiac sodium channel Na_v1.5 by tetrodotoxin and quinidine

Structural basis for pore blockade of the human cardiac sodium channel Na_v1.5 by tetrodotoxin and quinidine