Preferential block of inactivation-deficient Na+ currents by capsaicin reveals a non-TRPV1 receptor within the Na+ channel

Abstract

Capsaicin elicits burning pain via the activation of the vanilloid receptor (TRPV1). Intriguingly, several reports showed that capsaicin also inhibits Na + currents but the mechanisms remain unclear. To explore this non-TRPV1 action we applied capsaicin to HEK293 cells stably expressing inactivation-deficient rat skeletal muscle Na + mutant channels (rNav1.4-WCW). Capsaicin elicited a conspicuous time-dependent block of inactivation-deficient Na + currents. The 50% inhibitory concentration (IC 50 ) of capsaicin for open Na + channels at +30 mV was measured 6.8 ± 0.6 μM (n = 5), a value that is 10-30 times lower than those for resting (218 μM) and inactivated (74 μM) wildtype Na + channels. On-rate and off-rate constants for capsaicin open-channel block at +30 mV were estimated to be 6.37 μM −1 s −1 and 34.4 s −1 , respectively, with a calculated dissociation constant (K D ) of 5.4 μM. Capsaicin at 30 μM produced ~70% additional use-dependent block of remaining rNav1.4-WCW Na + currents during repetitive pulses at 1 Hz. Site-directed mutagenesis showed that the local anesthetic receptor was not responsible for the capsaicin block of the inactivation-deficient Na + channel. Interestingly, capsaicin elicited little time-dependent block of batrachotoxin-modified rNav1.4-WCW Na + currents, indicating that batrachotoxin prevents capsaicin binding. Finally, neuronal open Na + channels endogenously expressed in GH 3 cells were as sensitive to capsaicin block as rNav1.4 counterparts. We conclude that capsaicin preferentially blocks persistent late Na + currents, probably via a receptor that overlaps the batrachotoxin receptor but not the local anesthetic receptor. Drugs that target such a non-TRPV1 receptor could be beneficial for patients with neuropathic pain.

Ingestion of transient receptor potential channel agonists attenuates exercise‐induced muscle cramps

“…It is still possible that our findings are non‐TRP channel mediated because TRP agonists exert other effects. For example, both TRPV1 and TRPA1 agonists can inhibit voltage‐gated sodium channels, which could be another avenue through which muscle cramping is attenuated. However, oral consumption of TRP agonists in the amount employed in this study does not significantly increase plasma concentration of these agonists, supporting the assertion that the effects of TRP agonists are reflexive in nature.…”

Inhibitory Effects of Capsaicin on Voltage-Gated Potassium Channels by TRPV1-Independent Pathway

“…It is generally accepted that a drug-induced use-dependent block is attributed to the drug binding to a specific channel state (to the channel open stage, or to the inactivated state, thereby stabling the nonconducting channel state) (Savio-Galimberti et al 2012; Takeda et al 2006). Use-dependent block of capsaicin (30 µM) in neuronal Na + channels is related to direct capsaicin binding via non-TRPV1 receptor within the open Na + channel (Wang et al 2007). It is not known whether there is a non-TRPV1 receptor of capsaicin within open K + channels.…”

Vanilloid-Induced Conduction Analgesia: Selective, Dose-Dependent, Long-Lasting, with a Low Level of Potential Neurotoxicity

“…Voltage-clamp experiments showed that capsaicin inhibits Na + currents in specific types of ganglion neurons (46, 47). This effect might be related to TRPV1 or be independent of it, via changes in membrane elasticity (48) or via a non-TRPV1 receptor (49). Conduction blockade could be also associated with many other mechanisms of action demonstrated by vanilloid agonists (for example, insufficient energy supply due to mitochondrial dysfunction or inhibition of axonal transport).…”