2018 - Biophysical and Pharmacological Characterization of Voltage-Gated Sodium Channels Involved in Pain Pathways
SyncroPatch 384PE Oral Presentation Video
Dr. Markus Rapedius, Senior Scientist, Nanion Technologies
Webinar: "HTS Sodium Ion Channel Assays on the SyncroPatch 384PE"
May 08, 2018
Voltage-gated Na (NaV) channels expressed in dorsal root ganglion neurons (DRG) such as NaV1.7, NaV1.8 and NaV1.9 have been proposed to play important roles in nociception and pain signalling1. Besides NaV1.7, NaV1.8 and NaV1.9 are exclusively expressed in dorsal root ganglion (DRG) neurons where they have been associated in neuropathic and inflammatory pain1 or linked to inherited pain syndromes2. Whereas NaV1.7 plays a pivotal role in the modulation of action potential threshold, NaV1.8 channel is the predominant channel driving and shaping TTX-resistant action potentials (AP) in DRG neurons. Due to its relatively depolarized voltage dependence of inactivation, NaV1.8 can contribute to action potential generation even at depolarized membrane potentials which may occur during nerve injury or pain signalling3. This property, coupled with its location in DRG neurons and the modification of expression patterns in animal models of pain and human pain states, has meant that NaV1.8 has received attention as a novel target for pain therapeutics for chronic, inflammatory and neuropathic pain. Although NaV1.9 probably does not contribute to action potential amplitude, it most likely acts as a threshold channel, contributing to resting membrane potential and lowering the threshold for action potentials thereby increasing repetitive firing4. Gain-of function mutations in human pain disorders points to a role of NaV1.9 in pain sensation and transmission in humans. However, NaV1.7 is TTX-resistant and does exhibit distinguished biophysical characteristics such as fast inactivation and slow recovery from inactivation.
We have used automated patch clamp in combination with commercially available cell lines to investigate the activation and inactivation properties of NaV1.7, NaV1.8 and NaV1.9 in comparison. Furthermore, we have addressed pharmacological properties of different inactivated states of standard compounds. We are happy to provide examples for all three channels at high success rate ready for Drug Discovery.
1 Amaya, et al, 2000. Mol & Cell. Neurosci. 15:331-42
2 Theile JW and Cummins TR., FrontPharm; 2:54; 2011.
3 Clare, 2010. Expert Opin. Investig. Drugs. 19(1):45-62
4 Dib-Hajj, et al, 2015. Nat. Rev. Neurosci. 16(9): 511-519