Capsaicin Regulates Voltage-Dependent Sodium Channels by Altering Lipid Bilayer Elasticity

Abstract

At submicromolar concentrations, capsaicin specifically activates the TRPV1 receptor involved in nociception. At micro-to millimolar concentrations, commonly used in clinical and in vitro studies, capsaicin also modulates the function of a large number of seemingly unrelated membrane proteins, many of which are similarly modulated by the capsaicin antagonist capsazepine. The mechanism(s) underlying this widespread regulation of protein function are not understood. We investigated whether capsaicin could regulate membrane protein function by changing the elasticity of the host lipid bilayer. This was done by studying capsaicin's effects on lipid bilayer stiffness, measured using gramicidin A (gA) channels as molecular forcetransducers, and on voltage-dependent sodium channels (VDSC) known to be regulated by bilayer elasticity. Capsaicin and capsazepine (10 -100 M) increase gA channel appearance rate and lifetime without measurably altering bilayer thickness or channel conductance, meaning that the changes in bilayer elasticity are sufficient to alter the conformation of an embedded protein. Capsaicin and capsazepine promote VDSC inactivation, similar to other amphiphiles that decrease bilayer stiffness, producing use-dependent current inhibition. For capsaicin, the quantitative relation between the decrease in bilayer stiffness and the hyperpolarizing shift in inactivation conforms to that previously found for other amphiphiles. Capsaicin's effects on gA channels and VDSC are similar to those of Triton X-100, although these amphiphiles promote opposite lipid monolayer curvature. We conclude that capsaicin can regulate VDSC function by altering bilayer elasticity. This mechanism may underlie the promiscuous regulation of membrane protein function by capsaicin and capsazepine-and by amphiphilic drugs generally.

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

“…The potency difference in resting and inactivated block was ~3-fold. Despite the difference in the pulse protocol, our results are consistent with those reported by Lundbaek et al (2005). As in their report, the accuracy of these values may be limited because of the inadequate concentration range.…”

“…However, at a higher frequency (10-66 Hz), use-dependent phenotype of rNav1.4 Na + channels by capsaicin was observed (Lundbaek et al, 2005). Because of the rapid recovery time course for the open-channel block by capsaicin in inactivation-dependent Na + currents (Fig.…”

“…This drug at sub-micromolar concentrations specifically activates the vanilloid receptor (transient receptor potential V1 channel or TRPV1; Caterina et al, 1997). However, capsaicin at micro-to millimolar concentrations apparently modulates a wide variety of ion channels (for the list see Lundbaek et al, 2005). Interestingly, repeated topical applications of capsaicin cream (0.025-0.075%; or 82-246 μM) achieve modest pain relief in most patients with postherpetic neuralgia, postmastectomy pain, and diabetic neuropathy (Szallasi and Blumberg, 1999).…”

“…These findings implied that capsaicin may block action potentials through the Na + channel route. Recently, Lundbaek et al (2005) showed that capsaicin at 30 μM blocked 12% and 37%, respectively, of resting and inactivated rat skeletal muscle α-subunit Na + channels (rNav1.4) expressed in HEK293 cells. Because of capsaicin's general effects on many ion channels and on lipid bilayer stiffness, these authors concluded that the weak inhibition of rNav1.4 Na + currents by capsaicin is due to changes in membrane elasticity.…”

“…Following the experiments of Lundbaek et al (2005) and the modeling work of Lipkind and Fozzard (2005) we chose the rNav1.4 skeletal muscle Na + channels to study the blocking action of capsaicin and capsazepine. The chemical structures of these drugs are shown in Fig.…”