Pain drug discovery|Na1.8|钠通道筛选|新药筛选|疼痛模型的建立|hERG检测

There are 9 human sodium channels, including Nav1.1-Nav1.9. Nav1.5, Nav1.8 and Nav1.9 are tetrodotoxin (TTX) insensitive sodium channels, of which Nav1.8 is mainly expressed in small diameter C-fiber neurons of the Dorsal Root Ganglion (DRG). It is an important ion channel involved in chronic pain, atrial fibrillation, and Buga syndrome, and is a highly selective target of action for pain treatment. A representative of glycosylglycinamide derivative class A-803467 is a Nav1.8 high-affinity, highly selective blocker, blocking sodium channels in resting and inactivated states without significant frequency-dependent blockade, which can effectively inhibit neuropathic pain. The EPhys team in ICE has validated patch clamp method for human- and rat-derived Nav1.8 cell lines and action potentials (AP) of dorsal root ganglion neurons for drug screening.

Nav ChannelSubtypeCell LineSubunitGene SymbolSpecieshNav1.8Nav1.8-CHOα/β1/β3SCN10A/SCN1B/SCN3BHumanrNav1.8rNav1.8-ND7/23α/β3Scn10a/Scn3bRatrDRG●--Rat

Key Words:

Nav1.8

DRG

Pain

Manual Patch Clamp

Drug screening

Manual patch clamp validation-hNav1.8

Figure 1. Concentration-response curve and representative current traces of A803467 on hNav1.8 resting state (IC50=127.2nM)

Figure 2. Concentration-response curve and representative current traces of A803467 on hNav1.8 half-inactivated state (IC50=30.3nM)

Figure 3. Concentration-response curve and representative current traces of A803467 on rNav1.8 resting state (IC50=510.2nM)

Figure 4. Concentration-response curve and representative current traces of A803467 on rNav1.8 resting state (IC50=60.8nM)

Manual patch clamp validation-DRG neurons AP

Figure 5. Effects of A803467 on rDRG neurons action potential.

(A) AP traces in current clamp mode following a 1s 1.5× Rheobase current injection in the absence and presence of 10 µM A803467.

(B) Representative single AP trace recorded from control and 10 µM A803467.