Differential binding of tetrodotoxin and its derivatives to voltage‐sensitive sodium channel subtypes (Na<sub>v</sub>1.1 to Na<sub>v</sub>1.7)

Tsukamoto, Tadaaki; Chiba, Yukie; Wakamori, Minoru; Yamada, Tomoshi; Tsunogae, Shunsuke; Cho, Yuko; Sakakibara, Ryo; Imazu, Takuya; Tokoro, Shouta; Satake, Yuki; Adachi, Masaatsu; Nishikawa, Toshio; Yotsu‐Yamashita, Mari; Konoki, Keiichi

doi:10.1111/bph.13985

Cited by 56 publications

(58 citation statements)

References 47 publications

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“…), albeit more recent studies failed to replicate high‐potency inhibition of Na V 1.6 (Tsukamoto et al . ). Thus, novel approaches are needed to study Na V 1.6 channels in isolation in native neurons.…”

Section: Introductionmentioning

confidence: 97%

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Israel

Tanaka

Castro

et al. 2019

The Journal of Physiology

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Key points Voltage‐gated sodium channels are critical for peripheral sensory neuron transduction and have been implicated in a number of painful and painless disorders. The β‐scorpion toxin, Cn2, is selective for NaV1.6 in dorsal root ganglion neurons. NaV1.6 plays an essential role in peripheral sensory neurons, specifically at the distal terminals of mechanosensing fibres innervating the skin and colon. NaV1.6 activation also leads to enhanced response to mechanical stimulus in vivo. This works highlights the use of toxins in elucidating pain pathways moreover the importance of non‐peripherally restricted NaV isoforms in pain generation. Abstract Peripheral sensory neurons express multiple voltage‐gated sodium channels (NaV) critical for the initiation and propagation of action potentials and transmission of sensory input. Three pore‐forming sodium channel isoforms are primarily expressed in the peripheral nervous system (PNS): NaV1.7, NaV1.8 and NaV1.9. These sodium channels have been implicated in painful and painless channelopathies and there has been intense interest in them as potential therapeutic targets in human pain. Emerging evidence suggests NaV1.6 channels are an important isoform in pain sensing. This study aimed to assess, using pharmacological approaches, the function of NaV1.6 channels in peripheral sensory neurons. The potent and NaV1.6 selective β‐scorpion toxin Cn2 was used to assess the effect of NaV1.6 channel activation in the PNS. The multidisciplinary approach included Ca2+ imaging, whole‐cell patch‐clamp recordings, skin–nerve and gut–nerve preparations and in vivo behavioural assessment of pain. Cn2 facilitates NaV1.6 early channel opening, and increased persistent and resurgent currents in large‐diameter dorsal root ganglion (DRG) neurons. This promotes enhanced excitatory drive and tonic action potential firing in these neurons. In addition, NaV1.6 channel activation in the skin and gut leads to increased response to mechanical stimuli. Finally, intra‐plantar injection of Cn2 causes mechanical but not thermal allodynia. This study confirms selectivity of Cn2 on NaV1.6 channels in sensory neurons. Activation of NaV1.6 channels, in terminals of the skin and viscera, leads to profound changes in neuronal responses to mechanical stimuli. In conclusion, sensory neurons expressing NaV1.6 are important for the transduction of mechanical information in sensory afferents innervating the skin and viscera.

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Section: Introductionmentioning

confidence: 97%

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Israel

Tanaka

Castro

et al. 2019

The Journal of Physiology

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“…[29] Patch-clamp recordings were conducted using aw hole-cell recording configuration. [29] Patch-clamp recordings were conducted using aw hole-cell recording configuration.…”

Section: Whole-cell Patch-clamp Recordingsmentioning

confidence: 99%

Synthesis of C12‐Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage‐Gated Sodium Channels

Adachi

Yamada

Ishizuka

et al. 2020

Chemistry A European J

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An ovel series of C12-keto-type saxitoxin (STX) derivatives bearinga nu nusualn onhydrated form of the ketone at C12 has been synthesized,a nd their Na V -inhibitory activity has been evaluated in ac ell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX (3a)s howedp otent inhibitory activity againstn euroblastoma Neuro2Ai nboth cell-baseda nd electrophysiological analyses,w ithE C 50 and IC 50 valueso f8 .5 and 30.7 nm,r espectively.I nterestingly,t he compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of Na V 1.5, with an IC 50 value of 94.1 nm.D erivatives 3a-d and 3f showedl ow recovery rates from Na V 1.2 subtype (ca4 5-79 %) comparedt on atural dcSTX (2), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-ketod erivatives with Na V in which the enonem oiety in the STX derivatives 3 worksa sM ichaela cceptorf or the carboxylateo fA sp 1717 .

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“…Electrophysiology studies with naturally occurring Site 1 ligands against different wildtype and mutant NaV isoforms have identified the extracellular vestibule of NaV1.7 as a promising locus for selective inhibitor design. (31)(32)(33) The outer mouth of the channel is formed from residues that link the S5-S6 helices (referred to as pore loops) from each of the four domains. The domain III pore loop of human NaV1.7 contains a sequence variation, 1398T/1399I, that is not present in 20 other human NaV subtypes (which contain MD at equivalent position, Suppl Table 1).…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Selective, State-Independent Inhibitor of Na_V1.7 by Modification of Guanidinium Toxins

Pajouhesh

Beckley

Delwig

et al. 2019

Preprint

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The voltage-gated sodium channel isoform NaV1.7 is highly expressed in small diameter dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gainof-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These 20 35 addiction. Voltage-gated sodium ion channels (NaVs) have emerged as promising targets for the development of non-opioid pain medicines. NaVs are involved in the propagation of electrical signals along neurons throughout the body. Humans born without a functional copy of one sodium channel subtype, NaV1.7, are unable to experience most types of pain. In the present work, we disclose the discovery and characterization of a selective inhibitor of NaV1.7 that reduces 40 sensitivity to a painful thermal stimulus in non-human primates. Findings from this work may help guide the development of novel, non-addictive drug candidates as alternatives to opioids.

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Differential binding of tetrodotoxin and its derivatives to voltage‐sensitive sodium channel subtypes (Na_v1.1 to Na_v1.7)

Cited by 56 publications

References 47 publications

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Synthesis of C12‐Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage‐Gated Sodium Channels

Discovery of a Selective, State-Independent Inhibitor of Na_V1.7 by Modification of Guanidinium Toxins

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Differential binding of tetrodotoxin and its derivatives to voltage‐sensitive sodium channel subtypes (Nav1.1 to Nav1.7)

Cited by 56 publications

References 47 publications

NaV1.6 regulates excitability of mechanosensitive sensory neurons

NaV1.6 regulates excitability of mechanosensitive sensory neurons

Synthesis of C12‐Keto Saxitoxin Derivatives with Unusual Inhibitory Activity Against Voltage‐Gated Sodium Channels

Discovery of a Selective, State-Independent Inhibitor of NaV1.7 by Modification of Guanidinium Toxins

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Differential binding of tetrodotoxin and its derivatives to voltage‐sensitive sodium channel subtypes (Na_v1.1 to Na_v1.7)

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Na_V1.6 regulates excitability of mechanosensitive sensory neurons

Discovery of a Selective, State-Independent Inhibitor of Na_V1.7 by Modification of Guanidinium Toxins