Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

TRPV3 (Transient Receptor Potential Channel Subfamily V Member 3)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101877


Historical Background

TRPV3, a member of the subfamily V of transient receptor potential (TRP) channel family, was first identified as a temperature-sensitive nonselective cation channel by three independent research groups (Smith et al. 2002; Xu et al. 2002; Peier et al. 2002). TRPV3 channels have a large unitary conductance of about 150–200 pS and share 43% sequence homology with TRPV1, the capsaicin receptor. Like many other TRP channels, TRPV3 is a tetramer, and each subunit is composed of six transmembrane (TM) domains. The putative pore loop is located between TM5 and TM6 (Xu et al. 2002). TRPV3 is preferentially permeable to Ca2+, and its permeability ratio of Ca2+/Na+ is estimated to be around 10–15. Functional TRPV3 channel is present in both neuronal and non-neuronal tissues with a prominent expression in the skin, where it plays important roles in skin physiology and disease (Smith et al. 2002).

Activation and Modulation of TRPV3

As one of the temperature-sensitive TRP channels (also called thermoTRP channels), TRPV3 was initially found to be activated by warm temperatures in both innocuous and noxious ranges with a temperature activation threshold between 31 and 39 °C. Temperature activation of TRPV3 produces a large membrane current characterized by outward rectification and also elicits a robust Ca2+ influx in TRPV3-expressing heterologous cells (Smith et al. 2002; Xu et al. 2002; Peier et al. 2002). High-throughput screening of randomly mutagenized TRPV3 mutants has identified several critical amino acid residues in the TRPV3 channel pore region that are required for heat activation of the channel (Grandl et al. 2008) (Fig. 1). In addition to warm temperatures, TRPV3 is also activated by a synthetic compound 2-aminoethoxydiphenyl borate (2APB) and its structurally related analog diphenylboronic anhydride (DPBA). Further studies identified two amino acid residues (H426 and R696) in the intracellular N- and C-termini of mouse TRPV3 that are specifically required for the activation by 2APB (Fig. 1). Besides 2APB and its analogs, TRPV3 is activated by several natural compounds, such as camphor, carvacrol, eugenol, and incensole acetate (IA) (Luo and Hu 2014). In addition to these exogenous activators, TRPV3 is also activated by many endogenous ligands including farnesyl pyrophosphate (FPP) and protons (Luo and Hu 2014). Unlike TRPV1 which displays heat-induced desensitization in the presence of extracellular Ca2+, heat-induced activation of TRPV3 exhibits sensitization, i.e., TRPV3-mediated responses increase gradually with repeated heat stimulation (Xu et al. 2002; Peier et al. 2002). Similar to the temperature activation, TRPV3 also displays sensitization when challenged by repeated exposures to 2APB. The TRPV3 sensitization is a unique intrinsic property of the protein but not specific to any TRPV3 activators or regulation by intracellular signaling molecules, such as calmodulin (CaM) (Xiao et al. 2008).
TRPV3 (Transient Receptor Potential Channel Subfamily V Member 3), Fig. 1

Activation and modulation of TRPV3 channels. TRPV3 assembles as tetramers with each subunit comprising six transmembrane domains. TRPV3 can be activated by warm temperatures and chemical ligands including 2APB, camphor, and protons. The function of TRPV3 is modulated by many signaling molecules, such as Ca2+, Mg2+, ATP, CaM, and PIP2. The corresponding acting sites for TRPV3 activators and modulators are illustrated in the diagram

The function of TRPV3 is modulated by many bioactive molecules. It has been reported that the Ca2+-binding protein CaM binds to the TRPV3 ankyrin repeat domain and mediates the inhibition of the channel by intracellular Ca2+ (Xiao et al. 2008). Another divalent cation Mg2+ also inhibits TRPV3 overexpressed in heterologous cells or endogenously expressed by the primary epidermal keratinocytes. Moreover, TPRV3 function is inhibited by several intracellular signaling molecules. For instance, ATP, the molecular unit of energy currency of life, directly interacts with the N-terminal ankyrin repeat domain of TRPV3, and blocks the sensitization of the channel. PIP2 is an important phospholipid enriched in the plasma membrane, which modulates the functions of many ion channels including TRPV1, TRPM8, and the M-type K+ channel. Like its close relative TRPV1, TRPV3 function is potentiated by depletion of PIP2 through activation of several Gq/11-coupled receptors (Fig. 1). On the other hand, the function of TRPV3 is markedly enhanced by many unsaturated fatty acids including arachidonic acid which facilitates the activation of TRPV3 by 2APB (Luo and Hu 2014).

TRPV3 in Skin Physiology and Skin Disorders

TRPV3 is abundantly expressed by epidermal keratinocytes and plays a critical role in cutaneous homeostasis and skin diseases (Fig. 2). TRPV3 null mice exhibit defects in the skin barrier formation due to the impaired keratinocyte cornification, suggesting that TRPV3 function is required to form the skin barrier (Cheng et al. 2010). On the other hand, pharmacological activation of TRPV3 with 2APB or camphor had no affect on the barrier recovery after tape stripping, which might be due to the weak potency and poor selectivity of these compounds. Several lines of evidence have confirmed that TRPV3 is required for hair morphogenesis because global or keratinocyte-specific knockout of TRPV3 produces a wavy hair coat phenotype which is caused by impaired transforming growth factor alpha (TGF-α)/epidermal growth factor receptor (EGFR) signaling which plays critical roles in the terminal differentiation of suprabasal keratinocytes (Cheng et al. 2010). Consistent with the finding that TRPV3 is important to normal hair growth, gain-of-function TRPV3 mutations (G573S and G573C) result in a hairless phenotype in both mice and rats due to the constitutive activity of TRPV3 which produces intracellular Ca2+ overload-induced cellular toxicity of the keratinocytes (Asakawa et al. 2006). Animals carrying these gain-of-function TRPV3 mutations also exhibit downregulation of genes encoding several keratin-associated proteins that play critical roles in maintaining normal hair growth cycle. Similar to rodent TRPV3, human TRPV3 is also expressed by hair follicle keratinocytes located in the outer root sheath (ORS), activation of which inhibits hair growth, suggesting that TRPV3 is a critical regulator for hair growth in both rodents and humans (Borbiro et al. 2011).
TRPV3 (Transient Receptor Potential Channel Subfamily V Member 3), Fig. 2

Physiological and pathological roles of TRPV3 channels. TRPV3 is widely expressed in various tissues. In skin keratinocytes, TRPV3 contributes to the barrier formation, hair growth, and dermatitis and is also involved in the genesis of our senses of warmth, pain, and itch. In the cardiovascular system, activation of TRPV3 in the endothelia cells of arteries produces vascular dilation. TRPV3 is also expressed by the epithelial cells in the colon and has been identified as a risk factor for colorectal cancer

In addition to hair growth, TRPV3 also plays pivotal roles in skin inflammation (Fig. 2). When housed in a conventional environment the DS-Nh, mice spontaneously develop symptoms of atopic dermatitis (AD) including erythema, edema, dry skin, skin erosions, and excoriations, which A likely caused by Staphylococcus aureus (S. aureus). The spontaneously developed dermatitis has been recapitulated in the TRPV3Gly573Ser transgenic mice in which the Nh mutation is overexpressed under the control of the TRPV3 promoter, further supporting the causal relationship of overactive TRPV3 to inflammatory skin diseases (Yoshioka et al. 2009). In humans, multiple mutations in TRPV3 are associated with Olmsted syndrome characterized by the symmetric and mutilating palmoplantar keratoderma and periorificial keratotic plaques (Lin et al. 2012). The expression levels of TRPV3 and other TRPV channels are also significantly increased in erythematotelangiectatic rosacea-affected and phymatous rosacea-affected skin in human patients, supporting that TRPV3 is critically involved in the initiation and development of rosacea, a common chronic inflammatory skin disease of unknown etiology.

TRPV3 in Temperature, Pain, and Itch Sensations

There is little evidence for the existence of functional TRPV3 channels in mouse dorsal root ganglion (DRG) neurons, although TRPV3 mRNA transcripts are detected in monkey DRG neurons (Xu et al. 2002; Grandl et al. 2008). Nevertheless, TRPV3 knockout mice display impaired responses to innocuous and noxious heat but not other sensory modalities, suggesting a role of skin-expressed TRPV3 in sensing warm temperatures and heat pain in vivo (Moqrich et al. 2005). Consistent with this finding, mice with selective overexpression of TRPV3 in keratinocytes have shorter escape latencies compared with wild-type mice in response to noxious heat in the presence of a selective TRPV1 inhibitor, demonstrating a TRPV3-dependent higher sensitivity to noxious stimuli which likely is overridden by TRPV1 under normal condition (Fig. 2). On the other hand, acute thermal sensation is not abolished in either TRPV1 or TRPV3 single knockout mice, suggesting functional redundancies among various temperature-sensitive ion channels (Marics et al. 2014). Although the expression of TRPV3 is upregulated in the skin under some pain-related conditions, most of the evidence supporting a role of TRPV3 in pain sensation is based on the findings that administration of some TRPV3 activators could induce acute nocifensive responses in mice, which were suppressed by a few TRPV3 inhibitors. However, conclusions based on these studies rely largely on the specificity and selectivity of these activators and inhibitors. To further validate the role of TRPV3 in acute pain sensation, the use of TRPV3 knockout mice, especially conditional knockout mice, are necessary in future studies. Up to date, there is no evidence showing the direct involvement of TRPV3 in chronic inflammatory pain or neuropathic pain.

In humans, TRPV3 expression is significantly higher in the skin of atopic dermatitis patients associated with chronic pruritus compared with those without chronic itching. Recently, Kim et al. have also demonstrated that the expression and function of TRPV3 were increased in keratinocytes from the burn scars in patients with post-burn pruritus (Kim et al. 2016). These studies suggest that TRPV3 may contribute to the pathogenesis of chronic itching in some forms of dermatitis in humans (Fig. 2). Furthermore, the DS-Nh mice exhibit severe spontaneous scratching likely due to the constitutive activity of TRPV3. The spontaneous scratching in a mouse model of dry skin-associated chronic itch generated by acetone-ether-water (AEW) treatment was also markedly reduced in the TRPV3 knockout mice (Yamamoto-Kasai et al. 2012). Expression levels of both nerve growth factor (NGF) and thymic stromal lymphopoietin (TSLP), which have been shown to produce itch sensation, are increased in the skin of mice with gain-of-function TRPV3 mutations, suggesting that both NGF and TSLP might serve as the downstream signaling mediators of TRPV3-mediated chronic itch. Since it is known that TRPV3 is mainly expressed by epidermal keratinocytes but not itch-sensing primary sensory neurons, it is not clear how activation of TRPV3 in the keratinocytes leads to activation of pruriceptors and produces itch sensation. So far there is no evidence showing that direct activation of TRPV3 can evoke acute itch responses because of a lack of selective TRPV3 agonists and antagonists.

TRPV3 in Vascular Regulation

Although both immunohistochemical assays and functional studies using patch clamp and Ca2+ imaging techniques have confirmed the expression of TRPV3 in the endothelial cells of arteries, the presence of functional TRPV3 channels in the smooth muscle cells of artery wall still remains controversial. While TRPV3 immunoreactivity was detected in the smooth muscle layer in parenchymal artery, carvacrol did not evoke a Ca2+ response in rat pial artery smooth muscle cells. It should also be noted that different sources of antibodies were used in these studies, and no functional studies were carried out to characterize the endogenous TRPV3 channels in the smooth muscle cells of parenchymal artery (Pires et al. 2015). Further studies have demonstrated that activation of TRPV3 induces vascular dilation in these arteries, which is attenuated by disruption of endothelial cell layer or pharmacological inhibition of TRPV3. TRPV3-mediated Ca2+ influx subsequently activates intermediate (IK)- and small-conductance Ca2+-activated potassium (SK) channels, resulting in potassium efflux and hyperpolarization of the membrane potential of the endothelial cells. Hyperpolarization of endothelial cells will then decrease the membrane potential of the underlying smooth muscle cells via myoendothelial gap junctions leading to the relaxation of smooth muscle cells and dilation of the artery. Consistent with these findings, both IK and SK blockers attenuate the TRPV3-mediated vascular dilation. These studies suggest that TRPV3 might be a potential therapeutic target for the treatment of cardiovascular disorders such as hypertension and stroke (Fig. 2). In another study, Moussaieff et al. have demonstrated that incensole acetate, a major resin from Boswellia, protects against neurological damage in ischemia in mice via the activation of TRPV3, although it remains unknown whether endothelial or neuronal TRPV3 channels in the brain mediate the protective role of IA.

TRPV3 in Cancer

TRPV3 is highly expressed by epithelial cells in the alimental canal, and TRPV3 has been identified as a high-risk factor for colorectal cancer in a study examining the association between genetic variability of fatty acid metabolism-related genes and colorectal risk in colorectal cancer patients (Hoeft et al. 2010). However, so far there is no experimental data confirming the role of TRPV3 in the development of colorectal cancer. In addition to colorectal cancer, TRPV3 is also found to be upregulated in human non-small cell lung cancer. The expression of TRPV3 correlates with the differentiation and the tumor-node-metastasis (TNM) stage of the non-small cell lung cancer, and inhibition of TRPV3 leads to cell cycle arrest at the G1/S boundary and decreased proliferation of lung cancer cells (Li et al. 2016). As an androgen receptor target gene, TRPV3 is upregulated in prostate cancer cell line C4-2B when stimulated with dihydrotestosterone (Jariwala et al. 2007). Furthermore, TRPV3-mediated Ca2+ influx increases the expression and function of the endogenous antiangiogenic molecule thrombospondin 1 (TSP1), which promotes the migration of prostate tumor cells (Firlej et al. 2011). These studies suggest that TRPV3 might be a useful biological marker in the diagnosis and treatment of several types of cancers (Fig. 2).


TRPV3 is a Ca2+-permeable nonselective cation channel that is activated by both warm temperatures and chemical compounds and well regulated under both physiological and pathological conditions by many metal ions and intracellular signaling molecules. TRPV3 is functionally expressed in the skin where it plays important roles in hair growth and hair morphogenesis, cutaneous homeostasis, and inflammatory skin diseases. Like other pain- and itch-related thermoTRP channels, TRPV3 is also involved in the detection of temperature, pain, and itch signals, and TRPV3 antagonists are potential drug candidates for the treatment of both pain and itch conditions. In addition to epidermal keratinocytes, TRPV3 is also extensively expressed in vascular endothelial cells and mediates vascular dilation when activated, suggesting that TRPV3 agonists might be used for the treatment of hypertension-related cardiovascular diseases. The association between TRPV3 overexpression and various types of cancers suggests that TRPV3 function might be related to tumorigenesis, and TRPV3 may serve as a diagnostic or therapeutic target in the battle against cancers.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.The Center for the Study of Itch, Department of AnesthesiologyWashington University in Saint LouisSaint LouisUSA