NaV1.8 | sodium voltage-gated channel alpha subunit 10

Family:
Sodium channels

Subgroups:
NaV1.1-1.9

Topology:
Alpha subunits consist of four homologous domains (I-IV) with six transmembrane alpha helices (S1–S6) and a pore-forming loop. One a subunit may associate with 1 or 2 b subunits to make up the channel.

NaV1.8: Background Information

NaV1.8 is expressed specifically in the dorsal root ganglion (DRG), in unmyelinated, small-diameter sensory neurons called C-fibres, and is involved in nociception. C-fibres can be activated by noxious thermal or mechanical stimuli and thus can carry pain messages. The specific location of NaV1.8 in sensory neurons of the DRG may make it a key therapeutic target for the development of new analgesics and the treatment of chronic pain. NaV1.8 is a TTX-resistant sodium channel.

Gene:
SCN10A

Human Protein:
UniProt Q9Y5Y9

Tissue:
Brain (small diameter DRG neurons)

Function/ Application:
Excitability of neurons, nociceptive transmission

Pathology:
Neuropathic pain, Multiple Sclerosis

Accessory subunits:
b1, b2, b3

Interaction:
p11, PDZD2 and syntrophin-associated serine/threonine kinase (SASTK), Contactin, CAP-1A

Modulator:
Tetrodotoxin, lidocaine, benzocaine, A-887826, A-803467

Assays:
Patch Clamp: whole cell, room temperature, State- and use-dependence

Particularities:
NaV channel analysis requires GigaOhm seals and a stable and low access resistance

Recommended Reviews:
International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels. Pharmacol Rev 57: 397–409, Catterall, et al. 2005 

Data and Applications

NaV1.8 - I/V Characteristics

NaV18 IV Syncro384PEicon sp96   SyncroPatch 384PE (a predecessor model of SyncroPatch 384i) data and applications: 
The CHO cells were kindly provided by Charles River.

Raw traces from an exemplar cell expressing hNaV1.8 recorded on the SyncroPatch 384PE. Shown are current responses to increasing voltage steps from -60 to +60 mV (left). Current-voltage plot for an average of 380 cells is shown on the right. Shown are mean of peak amplitudes normalized to the maximum of each cell ± S.E.M. The data was fitted using a Boltzmann equation revealing a Vhalf of activation of -2.7 mV (n = 380), in good agreement with the range found in the literature.

NaV1.8 - State Dependent Inhibition

icon sp96   PE NaV1.8 State dep InhibitionSyncroPatch 384PE (a predecessor model of SyncroPatch 384i) data and applications:
Cells were kindly provided by Charles River.

The state dependent inhibition of Tetracaine on NaV1.8 currents were investigated. Measured on the SyncroPatch 384PE the perforated cell patch methodology (Escin) and multi-hole chips were used and compared to single-whole chips. Using a state dependant pulse protocol, the IC50 value determined from the first pulse (C1) was calculated as 54.3 µM (Hill coefficient = 1.50), and from the second pulse (C2) as 1.27 µM (Hill coefficient = 0.62). 

 

NaV1.8 - Voltage Dependent Block by Tetracaine

IC50 TetracaineOverlayicon pl   Patchliner data and applications:
Cells were kindly provided by Millipore.

Recordings were made on the Pachliner. The potency of tetracaine was affected by holding potential, becoming less potent with a more negative holding potential. Average concentration response curve for tetracaine, IC50 = 35 ± 8 μM (n = 3) for Vhold - 90 mV and 74 ± 15 μM (n = 4) for Vhold - 120 mV.

 

NaV1.8 - Tetracaine Pharmacology

ND723 Nav18 Tet Figureicon pl   Patchliner data and applications:
Cells were kindly provided by Millipore.

A Raw traces from an exemplar cell recorded on the Patchliner showing inhibition of current by increasing concentrations of tetracaine. Shown are current responses to a single step protocol to 20 mV for 25 ms from a holding potential of -90 mV. Current amplitude was completely recovered upon washout of tetracaine (red trace).
B Timeplot of the experiment.

NaV1.8 - Current-Voltage Relationship

ND723 PL Nav18 IV Figureicon pl   Patchliner data and applications:
Cells were kindly provided by Millipore.

A Raw traces from an exemplar cell recorded on the Patchliner. Shown are current responses to increasing voltage steps from -80 to +60 mV.
B Average current-voltage plot, Vhalf of activation was -9 mV (n = 19).
C Average inactivation plot, Vhalf of inactivation was -24 mV (n = 4). NaV1.8 currents started to activate at about -40 mV, peak response was elicited at around 20 mV.

Webinars and Movies

2018 - Biophysical and Pharmacological Characterization of Voltage-Gated Sodium Channels Involved in Pain Pathways

icon sp96   SyncroPatch 384PE (a predecessor model of the SyncroPatch 384i) Oral Presentation Video

Presenter: 
Dr. Markus Rapedius, Senior Scientist, Nanion Technologies

Application Notes

NaV1.8 - "Stability and reproducibility of hNaV1.8 recordings on Nanion's SyncroPatch 384PE"

icon sp96   SyncroPatch 384PE (a predecessor model of SyncroPatch 384i) application note   logo pdf   (1.4 MB)
Cells were kindly provided by Charles River.

NaV1.8 - "Characterization of rNaV1.8 (ND7-23) on Nanion's Patchliner"

icon pl   Patchliner application note:   logo pdf   (0.4 MB)
Cells were kindly provided by Millipore.

Posters

2018 - Investigating pain pathways by inhibition of voltage-gated sodium channels

icon sp96   SyncroPatch 384PE (a predecessor model of the SyncroPatch 384i) and   icon pl   Patchliner poster, FENS Meeting 2018  logo pdf   (2.5 MB)

Publications

2020 - Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker

icon sp96  SyncroPatch 384PE  (a predecessor model of the SyncroPatch 384i instrument) publication in Molecular Pharmacology (2020)

Authors:
A. Hinckley C., Kuryshev Y., Sers A., Barre A., Buisson B., Naik H., Hajos M.

2019 - Fenamates inhibit human sodium channel Nav1.7 and Nav1.8

icon pap   Port-a-Patch publication in Neuroscience Letters (2019)

Authors:
Sun, J-F., Xu, Y-J., Kong, X-H., Su, Y., Wang, Z-Y.

2018 - The opioid oxycodone use‐dependently inhibits the cardiac sodium channel Nav1.5

Icon CE   CardioExcyte 96 publication in British Journal of Pharmacology (2018)

Authors:
Meents J.E., Juhasz K., Stölzle-Feix S., Peuckmann-Post V., Rolke R. Lampert A.

2017 - A mutant of the Buthus martensii Karsch antitumor-analgesic peptide exhibits reduced inhibition to hNav1.4 and hNav1.5 channels while retaining analgesic activity

icon pap   Port-a-Patch publication in Journal of Biological Chemistry (2017)

Authors:
Xu Y., Meng X., Hou X., Sun J., Kong X., Sun Y., Liu Z., Ma Y., Niu Y., Song Y., Cui Y., Zhao M., Zhang J.

2012 - Isolation, characterization and total regioselective synthesis of the novel μO-conotoxin MfVIA from Conus magnificus that targets voltage-gated sodium channels

icon pap   Port-a-Patch publication in Biochemical Pharmacology (2012)

Authors: 
Vetter I., Dekan Z., Knapp O., Adams D.J., Alewood P.F., Lewis R.J.

 

 

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