Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a Ca2+ permeable non-selective cation channel activated by physical and chemical stimuli. Resiniferatoxin (RTX), an ultrapotent agonist of TRPV1, is under investigation for treatment of urinary bladder hyper-reflexia and chronic pain conditions. Here, we have determined the characteristics of RTX-induced responses in cells expressing native and cloned rat TRPV1. Whole-cell currents increase with repeated application of submaximal concentrations of RTX until a maximal response is attained and do not deactivate even after prolonged washout. Interestingly, the rate of activation and block by capsazepine of RTX-induced currents are significantly slower than for capsaicin-induced currents. RTX-induced whole-cell currents are outwardly rectifying, but to a lesser extent than capsaicin-induced currents. RTX-induced single channel currents exhibit multiple conductance states and outward rectification. The open probability (P o ) of RTX-induced currents is higher at all potentials as compared to capsaicin-induced currents, which showed a strong voltage-dependent decrease at negative potentials. Single-channel kinetic analyses reveal that open-time distribution of RTX-induced currents can be fitted with three exponential components at negative and positive potentials. The areas of distribution of the longer open time constants are significantly larger than capsaicin-induced currents. The closed-time distribution of RTX-induced currents can be fitted with three exponential components as compared to capsaicin-induced currents, which require four exponential components. Current-clamp experiments reveal that low concentrations of RTX caused a slow and sustained depolarization beyond threshold while generating few action potentials. Concentrations of capsaicin required for the same extent of depolarization generated a significantly greater number of action potentials. These properties of RTX may play a role in its clinical usefulness.

Characterization of the non‐adrenergic/non‐cholinergic response to perivascular nerve stimulation in the double‐perfused mesenteric bed of the mouse

“…Even in a depolarized state, the mouse arterial mesenteric bed responded to PNS via a TTX-or capsaicin-sensitive reduction of perfusion pressure. Interestingly, capsaicin activates the transient receptor potential vanilloid 1 (TRPV1) as recently reviewed by Begg et al (2005) whereas Raisinghani et al (2005) have suggested that binding of capsaicin to its receptors can occur in a voltage-dependent fashion in patch-clamped-single-cell experiments. Our results on NANC-induced reduction in perfusion pressure in a complex vascular circuit under depolarized conditions can therefore be explained by the voltage-dependent increases in TRPV1 activation as previously put forward by Raisinghani et al (2005).…”

Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway

“…Several reports have indicated that the anti-cancer effects of capsaicin are not to activate TRPV1 (Raisinghani et al, 2005), but to inhibit plasma membrane NADH oxidase (Morre et al, 1995). Moreover, alternative anti-cancer mechanisms of capsaicin have been associated with the production of reactive oxygen species (Qiao et al, 2005) and the reduction of TNF-α .…”

Ablation and Regeneration of Peripheral and Central TRPV1 Expressing Nerve Terminals and the Consequence of Nociception

“…Resiniferatoxin (RTX) is an ultrapotent TRPV1 agonist, which activates TRPV1 in an irreversible manner. As a result, TRPV1 nerve terminals are ablated by persistent increase in Ca 2+ influx [5,[23][24][25]. Therefore, it would be useful to use RTX to target TRPV1 to *Address correspondence to these authors at the Department of Clinical Medicine, Michigan State University, Lansing, MI 48824, USA; Tel: 217-545-2179; Fax: 217-545-0145; E-mails: lpremkumar@siumed.edu and sqyu@msu.edu treat conditions such as peripherally mediated inflammatory pain including shingles, urinary bladder hyperreflexia, deiabetic peripheral neuropathy, arthritis etc.…”