Hydrophobic Drug/Toxin Binding Sites in Voltage-Dependent K+ and Na+ Channels

Theemsche, Kenny M. Van; Sande, Dieter V. Van de; Snyders, Dirk J.; Labro, Alain J.

doi:10.3389/fphar.2020.00735

Cited by 14 publications

(6 citation statements)

References 146 publications

(228 reference statements)

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“…LAs interact with intracellular residues of Na + channels. 37 As LAs are weak bases, alkalinization of the LA-solution increases inhibition of sodium channels due to an increased membrane-permeability. 38 To test if this mode of accessibility also applies for the weak bases CQ and HCQ, the pH-value of the extracellular medium was set to 9.0.…”

Section: Resultsmentioning

confidence: 99%

“…LAs inhibit Na + channels by locking the pore from the intracellular side during the open state and are therefore described as use-dependent open state block. 37 At physiological pH-values, most LAs are predominantly positively charged due to protonation and have to be deprotonated into their neutral form before crossing the cell membrane. Alkalization of the extracellular medium changes the ratio between the two states in favor of the deprotonated form leading to an increased membrane permeability and pharmacological effect.…”

Section: Discussionmentioning

confidence: 99%

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Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

Hage¹,

Vries²,

Leffler³

et al. 2022

JEP

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Introduction: Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ) are successfully deployed for different diseases beyond the prophylaxis and treatment of malaria. Both substances exhibit antiviral properties and have been proposed for prophylaxis and treatment of COVID-19 caused by SARS-CoV-2. CQ and HCQ cause similar adverse events including life-threatening cardiac arrhythmia generally based on QT-prolongation, which is one of the most reported adverse events for both agents associated with the treatment of COVID-19. Various drugs known to induce QT-prolongation have been proven to exert local anesthetic (LA)-like properties regarding their impact on the cardiac Na + channel Nav1.5. Inhibition of Nav1.5 is considered as the primary mechanism of cardiotoxicity caused by LAs. However, the mechanism of the arrhythmogenic effects of CQ and HCQ related to Nav1.5 has not yet been fully investigated. Therefore, the exact mechanism of how CQ and HCQ affect the sodium currents generated by Nav1.5 need to be further elucidated. Objective: This in vitro study aims to investigate the effects of CQ and HCQ on Nav1.5-generated sodium currents to identify possible LA-like mechanisms that might contribute to their arrhythmogenic properties. Methods: The effects of CQ and HCQ on Nav1.5-generated sodium currents by HEK-293 cells expressing either wild-type human Nav1.5 or mutant Nav1.5 F1760A are measured using the whole-cell patch-clamp technique. Results: Both agents induce a state-dependent inhibition of Nav1.5. Furthermore, CQ and HCQ produce a use-dependent block of Nav1.5 and a shift of fast and slow inactivation. Results of experiments investigating the effect on the LA-insensitive mutant Nav1.5-F1760A indicate that both agents at least in part employ the proposed LA-binding site of Nav1.5 to induce inhibition. Conclusion:This study demonstrated that CQ and HCQ exert LA-typical effects on Nav1.5 involving the proposed LA binding site, thus contributing to their arrhythmogenic properties.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

Hage¹,

Vries²,

Leffler³

et al. 2022

JEP

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“…Landmark structure–function studies have shed light on the molecular mechanism of actions of prototypical gating-modifier spider-venom peptides ( 55 , 56 ). Amphipathic tarantula toxins partially partition into the membrane and interact with extracellular protein–lipid interfaces of voltage-sensor domains binding to the paddle motif (S3b helices, S3–S4 linkers, and S4 helices), and hence are also called voltage-sensor toxins ( 12 , 46 , 55 – 58 ). Pm1a’s sequence, structure, and functional modification of Na V and K V channel gating are consistent with the action of voltage-sensor toxins.…”

Section: Discussionmentioning

confidence: 99%

Multitarget nociceptor sensitization by a promiscuous peptide from the venom of the King Baboon spider

Finol‐Urdaneta

Ziegman

Dekan

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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The King Baboon spider, Pelinobius muticus, is a burrowing African tarantula. Its impressive size and appealing coloration are tempered by reports describing severe localized pain, swelling, itchiness, and muscle cramping after accidental envenomation. Hyperalgesia is the most prominent symptom after bites from P. muticus, but the molecular basis by which the venom induces pain is unknown. Proteotranscriptomic analysis of P. muticus venom uncovered a cysteine-rich peptide, δ/κ-theraphotoxin-Pm1a (δ/κ-TRTX-Pm1a), that elicited nocifensive behavior when injected into mice. In small dorsal root ganglion neurons, synthetic δ/κ-TRTX-Pm1a (sPm1a) induced hyperexcitability by enhancing tetrodotoxin-resistant sodium currents, impairing repolarization and lowering the threshold of action potential firing, consistent with the severe pain associated with envenomation. The molecular mechanism of nociceptor sensitization by sPm1a involves multimodal actions over several ion channel targets, including NaV1.8, KV2.1, and tetrodotoxin-sensitive NaV channels. The promiscuous targeting of peptides like δ/κ-TRTX-Pm1a may be an evolutionary adaptation in pain-inducing defensive venoms.

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“…CTXs and BTXs bind to site 5 of VGSCs, inducing an open state, subsequently allowing Na + passage inside cells. VGSC site 5 is comprised of the transmembrane segments S6 and S5 of the α-subunit domains I and IV, respectively [ 32 , 112 ]. CTXs bind to this site from the intracellular side of VGSCs ( Figure 2 ) [ 77 ].…”

Section: Mechanism Of Action and Toxicity: The Need For Predefined To...mentioning

confidence: 99%

Current Trends and New Challenges in Marine Phycotoxins

et al. 2022

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Marine phycotoxins are a multiplicity of bioactive compounds which are produced by microalgae and bioaccumulate in the marine food web. Phycotoxins affect the ecosystem, pose a threat to human health, and have important economic effects on aquaculture and tourism worldwide. However, human health and food safety have been the primary concerns when considering the impacts of phycotoxins. Phycotoxins toxicity information, often used to set regulatory limits for these toxins in shellfish, lacks traceability of toxicity values highlighting the need for predefined toxicological criteria. Toxicity data together with adequate detection methods for monitoring procedures are crucial to protect human health. However, despite technological advances, there are still methodological uncertainties and high demand for universal phycotoxin detectors. This review focuses on these topics, including uncertainties of climate change, providing an overview of the current information as well as future perspectives.

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Hydrophobic Drug/Toxin Binding Sites in Voltage-Dependent K+ and Na+ Channels

Cited by 14 publications

References 146 publications

Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

Multitarget nociceptor sensitization by a promiscuous peptide from the venom of the King Baboon spider

Current Trends and New Challenges in Marine Phycotoxins

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