Farnesyl Pyrophosphate Is a Novel Pain-producing Molecule via Specific Activation of TRPV3

Abstract

Temperature-sensitive transient receptor potential ion channels (thermoTRPs) expressed in epidermal keratinocytes and sensory afferents play an important role as peripheral pain detectors for our body. Many natural and synthetic compounds have been found to act on the thermoTRPs leading to altered nociception, but little is known about endogenous painful molecules activating TRPV3. Here, we show that farnesyl pyrophosphate (FPP), an intermediate metabolite in the mevalonate pathway, specifically activates TRPV3 among six thermoTRPs using Ca 2؉ imaging and electrophysiology with cultured keratinocytes and TRPV3-overexpressing cells. Agonistic potencies of related compounds in the FPP metabolism were ignorable. Voltage-dependence of TRPV3 was shifted by FPP, which appears to be the activation mechanism. An intraplantar injection of FPP acutely elicits nociceptive behaviors in inflamed animals, indicating that FPP is a novel endogenous pain-producing substance via TRPV3 activation. Co-culture experiments demonstrated that this FPP-evoked signal in the keratinocytes is transmitted to sensory neurons. In addition, FPP reduced TRPV3 heat threshold resulting in heightened behavioral sensitivity to noxious heat. Taken together, our data suggest that FPP is the firstly identified endogenous TRPV3 activator that causes nociception. Our results may provide useful chemical information to elucidate TRPV3 physiology and novel pain-related metabolisms.Skin keratinocytes and sensory neurons express sensor ion channels that detect changes in the external or internal environments. TRPV3 channel has been found to be expressed in the skin keratinocytes of mice and humans and in the sensory neurons of humans and is activated by temperatures exceeding 33°C (1-3). Studies using TRPV3-knock-out mice or TRPV3-overexpressing transgenic mice have demonstrated that TRPV3 is involved in behavioral responses to innocuous and noxious heat (4 -5).Searching for pharmacological tools to modulate TRPV3 activity seems active (see review, Ref. 6). Several phytosubstances and synthetic compounds, such as camphor, menthol, carvacrol, citral, incensole acetate, and 2-aminoethoxydiphenyl borate (2-APB) 2 are shown to activate TRPV3 (4, 7-13). It has been reported that some of endogenous molecules are able to modulate TRPV3 activation. For example, unsaturated fatty acids potentiated TRPV3 activation by 2-APB (14). S-Nitrosylation of the channel protein activates TRPV3, as well as other TRPVs (15). Ca 2ϩ and calmodulin suppressed the sensitization of TRPV3 to recurrent stimuli (16). However, little is known about endogenous compounds that are able to directly and specifically activate TRPV3.A variety of metabolites are formed in the human body as a result of the diverse biochemical processes and some of the metabolites are potentially involved in pain development (17). Farnesyl pyrophosphate (FPP) is an intermediate molecule in the cholesterol synthesis pathway. In the present study, we examined whether FPP is an activator for TRPV3. We performed Ca 2ϩ ...

The Ca2+-Permeable Cation Transient Receptor Potential TRPV3 Channel: An Emerging Pivotal Target for Itch and Skin Diseases

“…Both 17R-RvD1, a proresolving lipid mediator, and isopentenyl pyrophosphate can effectively reduce inflammatory pain induced by the intradermal injection of complete Freund's adjuvant in mice, whereas farnesyl pyrophosphate causes an acute irritative response (Bang et al, 2011). In addition, silencing of TRPV3 by small hairpin RNA in epidermal keratinocytes significantly abolishes these effects (Bang et al, 2010). Certain TRPV3 antagonists are now under development in clinical phase I and II clinical trials as potential analgesic agents.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Knockdown of TRPV3 with shRNA reduced nocifensive behavior induced by intraplanar injection of farnesyl pyrophosphate (structure shown in Fig. 8), a TRPV3 agonist, in inflamed rats and also blocked farnesyl pyrophosphateinduced thermal hyperalgesia (Bang et al, 2010). Hydra Biosciences has reported efficacy of TRPV3 receptor antagonists in models of inflammatory pain (CFA), formalin-induced flinching, thermal injury, and spinal sensitization (see Reilly and Kym, 2011).…”

Crystal structure of the N-terminal ankyrin repeat domain of TRPV3 reveals unique conformation of finger 3 loop critical for channel function

“…TRPV3-knockout mice have deficits in response to innocuous and noxious heat, suggesting the participation of TRPV3 in thermosensation and nociception (Moqrich et al, 2005). Like other TRPV channels, TRPV3 is a multimodal cation channel, and can be activated by natural compounds such as camphor, thymol (Moqrich et al, 2005;Xu et al, 2006), endogenou s ligands farnesyl pyrophosphate (FPP), NO (Yoshida et al, 2006;Bang et al, 2010), and a synthetic small molecules 2-APB (Chung et al, 2004a;Hu et al, 2004Hu et al, , 2009). TRPV3 has two distinct features.…”