Dataset Information

Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na_V1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome.

ABSTRACT: The human nociceptor-specific voltage-gated sodium channel 1.7 (hNa_V1.7) is critical for sensing various types of somatic pain, but it appears not to play a primary role in acute visceral pain. However, its role in chronic visceral pain remains to be determined. We used assay-guided fractionation to isolate a novel hNa_V1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNa_V1.7 (IC₅₀ = 10 nM), with greater than 100-fold selectivity over hNa_V1.3-hNa_V1.6, 45-fold selectivity over hNa_V1.1, and 24-fold selectivity over hNa_V1.2. Tsp1a is a gating modifier that inhibits Na_V1.7 by inducing a hyperpolarizing shift in the voltage-dependence of channel inactivation and slowing recovery from fast inactivation. NMR studies revealed that Tsp1a adopts a classical knottin fold, and like many knottin peptides, it is exceptionally stable in human serum. Remarkably, intracolonic administration of Tsp1a completely reversed chronic visceral hypersensitivity in a mouse model of irritable bowel syndrome. The ability of Tsp1a to reduce visceral hypersensitivity in a model of irritable bowel syndrome suggests that pharmacological inhibition of hNa_V1.7 at peripheral sensory nerve endings might be a viable approach for eliciting analgesia in patients suffering from chronic visceral pain.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC8369682 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Pharmacological Inhibition of the Voltage-Gated Sodium Channel NaV1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome.

Jiang Yan Y Castro Joel J Blomster Linda V LV Agwa Akello J AJ Maddern Jessica J Schober Gudrun G Herzig Volker V Chow Chun Yuen CY Cardoso Fernanda C FC Demétrio De Souza França Paula P Gonzales Junior J Schroeder Christina I CI Esche Steffen S Reiner Thomas T Brierley Stuart M SM King Glenn F GF

ACS pharmacology & translational science 20210607 4

The human nociceptor-specific voltage-gated sodium channel 1.7 (hNaV1.7) is critical for sensing various types of somatic pain, but it appears not to play a primary role in acute visceral pain. However, its role in chronic visceral pain remains to be determined. We used assay-guided fractionation to isolate a novel hNaV1.7 inhibitor, Tsp1a, from tarantula venom. Tsp1a is 28-residue peptide that potently inhibits hNaV1.7 (IC50 = 10 nM), with greater tha ...[more]

PMID: 34423271

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Project description:The human TE671 cell line was originally used as a model of medulloblastoma but has since been reassigned as rhabdomyosarcoma. Despite the characterised endogenous expression of voltage-sensitive sodium currents in these cells, the specific voltage-gated sodium channel (VGSC) subtype underlying these currents remains unknown. To profile the VGSC subtype in undifferentiated TE671 cells, endpoint and quantitative reverse transcription-PCR (qRT-PCR), western blot and whole-cell patch clamp electrophysiology were performed. qRT-PCR profiling revealed that expression of the SCN9A gene was ∼215-fold greater than the SCN4A gene and over 400-fold greater than any of the other VGSC genes, while western blot confirmed that the dominant SCN9A RNA was translated to a protein with a molecular mass of ∼250 kDa. Elicited sodium currents had a mean amplitude of 2.6 ± 0.7 nA with activation and fast inactivation V50 values of -31.9 ± 1.1 and -69.6 ± 1.0 mV, respectively. The currents were completely and reversibly blocked by tetrodotoxin at concentrations greater than 100 nm (IC50 = 22.3 nm). They were also very susceptible to the NaV 1.7 specific blockers Huwentoxin-IV and Protoxin-II with IC50 values of 14.6 nm and 0.8 nm, respectively, characteristic of those previously determined for NaV 1.7. Combined, the results revealed the non-canonical and highly dominant expression of NaV 1.7 in the human TE671 rhabdomyosarcoma cell line. We show that the TE671 cell line is an easy to maintain and cost-effective model for the study of NaV 1.7, a major target for the development of analgesic drugs and more generally for the study of pain. KEY POINTS: Undifferentiated TE671 cells produce a voltage-sensitive sodium current when depolarised. The voltage-gated sodium channel isoform expressed in undifferentiated TE671 cells was previously unknown. Through qRT-PCR, western blot and toxin pharmacology, it is shown that undifferentiated TE671 cells dominantly (>99.5%) express the NaV 1.7 isoform that is strongly associated with pain. The TE671 cell line is, therefore, a very easy to maintain and cost-effective model to study NaV 1.7-targeting drugs.

Dataset Information

Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na_V1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome.

Publications

Pharmacological Inhibition of the Voltage-Gated Sodium Channel Na<sub>V</sub>1.7 Alleviates Chronic Visceral Pain in a Rodent Model of Irritable Bowel Syndrome.

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