Correction: Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms

Bohannon, Briana M; Cruz, A.; Wu, X; Jowais, Jessica; Perez, Marta E.; Dykxhoorn, Derek M.; Liin, Sara I.; Larsson, H. Peter

doi:10.7554/elife.60141

Cited by 4 publications

(3 citation statements)

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“…Another study showed that EPA (eicosapentaenoic acid) effectively inhibited Na V in a dose-dependent manner and shifted the steady-state inactivation curve to the hyperpolarizing direction, which resulted in a reduced sodium window current (Liu et al, 2018). These studies suggest that fatty acids dock their hydrophobic chain in the fenestrations and let its charged head interact with sodium ions blocking its conduction through the pore (Bohannon et al, 2020).…”

Section: Fenestrations As Lipids Binding Sitesmentioning

confidence: 98%

Fenestropathy of Voltage-Gated Sodium Channels

El-Din

Lenaeus

2022

Front. Pharmacol.

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Voltage-gated sodium channels (Nav) are responsible for the initiation and propagation of action potentials in excitable cells. From pain to heartbeat, these integral membrane proteins are the ignition stations for every sensation and action in human bodies. They are large (>200 kDa, 24 transmembrane helices) multi-domain proteins that couple changes in membrane voltage to the gating cycle of the sodium-selective pore. Nav mutations lead to a multitude of diseases - including chronic pain, cardiac arrhythmia, muscle illnesses, and seizure disorders - and a wide variety of currently used therapeutics block Nav. Despite this, the mechanisms of action of Nav blocking drugs are only modestly understood at this time and many questions remain to be answered regarding their state- and voltage-dependence, as well as the role of the hydrophobic membrane access pathways, or fenestrations, in drug ingress or egress. Nav fenestrations, which are pathways that connect the plasma membrane to the central cavity in the pore domain, were discovered through functional studies more than 40 years ago and once thought to be simple pathways. A variety of recent genetic, structural, and pharmacological data, however, shows that these fenestrations are actually key functional regions of Nav that modulate drug binding, lipid binding, and influence gating behaviors. We discovered that some of the disease mutations that cause arrhythmias alter amino acid residues that line the fenestrations of Nav1.5. This indicates that fenestrations may play a critical role in channel’s gating, and that individual genetic variation may also influence drug access through the fenestrations for resting/inactivated state block. In this review, we will discuss the channelopathies associated with these fenestrations, which we collectively name “Fenestropathy,” and how changes in the fenestrations associated with the opening of the intracellular gate could modulate the state-dependent ingress and egress of drugs binding in the central cavity of voltage gated sodium channels.

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Section: Fenestrations As Lipids Binding Sitesmentioning

confidence: 98%

Fenestropathy of Voltage-Gated Sodium Channels

El-Din

Lenaeus

2022

Front. Pharmacol.

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“…Another lipid raft modulator, methyl beta-cyclodextrin, has been found to dissociate Na v from lipid rafts . In addition to most of the plasma membrane proteins, − the role of boundary lipids is also important for Na v ; thus, the inhibition of ion channels by fatty acids is not limited to Na v. ,− Accordingly, the inhibition of Na v by PUFAs observed in the present study might reveal the nonspecific aspect of their mode of action.…”

Section: Discussionmentioning

confidence: 57%

State-Dependent Inhibition of Voltage-Gated Sodium Channels in Neuroblastoma Neuro-2A Cells by Arachidonic Acid from Halichondria okadai

Chiba

Shimada

Yoshio

et al. 2022

Chem. Res. Toxicol.

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Voltage-gated sodium channels (Nav) are closely associated with epilepsy, cardiac and skeletal muscle diseases, and neuropathic pain. Several toxic compounds have been isolated from the marine sponge Halichondria okadai; however, toxic substances that modulate Nav are yet to be identified. This study aimed to identify Nav inhibitors from two snake venoms and H. okadai using mouse neuroblastoma Neuro-2A cells (N2A), which primarily express the specific Nav subtype Nav1.7, using whole-cell patch-clamp recordings. We successfully isolated arachidonic acid (AA, 1) from the hexane extract of H. okadai, and then the fatty acid-mediated modulation of Nav in N2A was investigated in detail for the first time. Octanoic acid (2), palmitic acid (3), and oleic acid (4) showed no inhibitory activity at 100 μM, whereas AA (1), dihomo-γ-linolenic acid (DGLA, 5), and eicosapentaenoic acid (EPA, 6) showed IC50 values of 6.1 ± 2.0, 58 ± 19, and 25 ± 4.0 μM, respectively (N = 4, mean ± SEM). Structure and activity relationships were investigated for the first time using two ω-3 polyunsaturated fatty acids (PUFAs), EPA (6) and eicosatetraenoic acid (ETA, 7), and two ω-6 PUFAs, AA (1) and DGLA (5), to determine their effects on a resting state, activated state, and inactivated state. Steady-state analysis showed that the half inactivation potential was largely hyperpolarized by 10 μM AA (1), while 50 μM DGLA (5), 50 μM EPA (6), and 10 μM ETA (7) led to a slight change. The percentages of the resting state block were 24 ± 1, 22 ± 1, 34 ± 4, and 38 ± 9% in the presence of AA (1), DGLA (5), EPA (6), and ETA (7), respectively, with EPA (6) and ETA (7) exhibiting a greater inhibition than both AA (1) and DGLA (5), and their inhibitions did not increase in the following depolarization pulses. None of the compounds exhibited the use-dependent block. The half recovery times from the inactivated state for the control, AA (1), DGLA (5), EPA (6), and ETA (7) were 7.67 ± 0.33, 34.3 ± 1.10, 15.5 ± 1.10, 10.7 ± 0.31, and 3.59 ± 0.18 ms, respectively, with AA (1) exhibiting a distinctively large effect. Overall, distributed binding to the resting and the inactivated states of Nav would be significant for the inhibition of Nav, which presumably depends on the active structure of each PUFA.

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“…The class IA antiarrhythmic drugs (e.g., procainamide) and the class IB antiarrhythmic drugs (e.g., lidocaine) might act on a smaller surface of the central cavity of the pore as well [5]. However, polyunsaturated fatty acids (PUFAs) and PUFA analogs have been shown to be antiarrhythmic by inhibiting Na v 1.5 channel currents, probably through acting on the voltage-sensing S4 segments that control inactivation in these channels [6,7].…”

Section: Introductionmentioning

confidence: 99%

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

Daimi

Lozano-Velasco

Aránega

et al. 2022

IJMS

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Nav1.5 is the predominant cardiac sodium channel subtype, encoded by the SCN5A gene, which is involved in the initiation and conduction of action potentials throughout the heart. Along its biosynthesis process, Nav1.5 undergoes strict genomic and non-genomic regulatory and quality control steps that allow only newly synthesized channels to reach their final membrane destination and carry out their electrophysiological role. These regulatory pathways are ensured by distinct interacting proteins that accompany the nascent Nav1.5 protein along with different subcellular organelles. Defects on a large number of these pathways have a tremendous impact on Nav1.5 functionality and are thus intimately linked to cardiac arrhythmias. In the present review, we provide current state-of-the-art information on the molecular events that regulate SCN5A/Nav1.5 and the cardiac channelopathies associated with defects in these pathways.

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Correction: Polyunsaturated fatty acid analogues differentially affect cardiac NaV, CaV, and KV channels through unique mechanisms

Cited by 4 publications

References 0 publications

Fenestropathy of Voltage-Gated Sodium Channels

Fenestropathy of Voltage-Gated Sodium Channels

State-Dependent Inhibition of Voltage-Gated Sodium Channels in Neuroblastoma Neuro-2A Cells by Arachidonic Acid from Halichondria okadai

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

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