Transient Receptor Potential Vanilloid (TRPV) channels are expressed in various skin cells, including non-neuronal cell types such as epidermal keratinocytes. They are polymodal sensors of the environment, regulating physiological function in response to a wide variety of stimuli. Indeed, in addition to their significant role in thermal responses and thermoregulation, TRPV channels are also implicated in local skin inflammation processes. Thus, these calcium permeable channels are associated to multiples skin diseases with inflammation, such as atopic dermatitis or psoriasis. In this chapter, we will mainly focus on TRPV1 and TRPV3 channels, as emerging pivotal targets for maintaining skin homeostasis in psoriasis-related inflammation.
- calcium channel
Skin is the largest organ of human organism, approximately 2m2. This envelop, in constant contact with the environment, can be divided into three layers: a deep layer, the hypodermis; then an intermediate layer, the dermis; and finally, a superficial layer, the epidermis. This top layer is mainly constituted of keratinocytes, which form the first physical and chemical barrier between the external environment and our body. To maintain this function, keratinocytes undergo a multistep process of differentiation, from proliferating cells of the
Despite its major keratinocyte content, epidermis is also composed of other cell populations in order to ensure protection of our organisms [1, 2]. Its immunity is guaranteed by Langerhans cells, a dendritic cell that contributes to innate and adaptative immunity [1, 2]. The sensory nerve endings passing through the epidermis (C-fibers and Aδ-fibers) were thought to be the exclusive transducers for the detection of environmental factors such as heat and pain, but Merkel cells can also act as mechanosensors . Free intra-epidermal sensory nerve endings are all unmyelinated: C-fibers are unmyelinated, while Aδ-fibers lose their myelination when they enter the epidermis, allowing them to come into direct contact with the epidermal keratinocytes (Figure 1A) . Therefore, in addition to the intra-epidermal sensory nerve endings, the epidermal keratinocytes also function as a sensory hub, able to detect environmental changes [5, 6]. Finally, the epidermis is constituted by another cell population: the melanocytes, located in the basal layer. With one for 4–10 keratinocytes, melanocytes provide a barrier from ultraviolet (UV) thanks to their ability to produce melanin, a photoprotector pigment [1, 2]. Opposite to the epidermis, the dermis is mainly composed of extracellular matrix produced by dermal fibroblasts. This intermediate layer also supports dermal blood vessels, nerve fibers, and epidermal appendages (pilosebaceous unit and sweat glands). Finally, hypodermis is composed of adipocytes separated by connective tissue. This deep layer insulates and protects the skin from mechanical injuries [1, 2]. Thus, the skin allows a protection against externals insults (ultraviolet, pathogens, mechanical pressure, etc.…) but also contributes to the maintenance of homeostasis such as information transfer, vitamin and metabolites secretions, hydric and thermal regulation.
To cope with various externals constrains, various cells of the skin express transmembrane sensors called Transient Receptor Potential (TRP) channels, which are involved in thermosensation, chemosensation, nociception, and mechanosensation . TRP channels can be divided into six subfamilies: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPV (vanilloid). Although TRPV channels have a major role in thermosensation , they also contribute to keratinocyte differentiation, skin barrier formation, and permeability thanks to calcium regulation. However, it appears that an aberrant TRP channel expression and function might contribute to some skin inflammatory diseases. In this review, we will focus on TRPV1 and TRPV3 structures, activation mechanisms, and their physiological roles in skin. We will also provide a new approach to study TRPV1 and TRPV3 channels in a very common chronic inflammatory disease, such as psoriasis.
2. TRPV1 and TRPV3 structure and gating
2.1 Expression and genetics
Among the six members of TRPV channels, thermosensors TRPV1 and TRPV3 are calcium channel both highly expressed in the skin, with different cells types expression (Figure 1B). The TRPV1 channel was firstly described on nociceptive sensory nerves from Dorsal Root sensory Ganglia (DRG) by Caterina
Unlike TRPV1, TRPV3 channels tissue expression is more restricted. Peier
TRPV1 (chr17:3,565,446-3,609,411) and TRPV3 (chr17:3,513,190-3,557,805) genes exist in tandem on human chromosome 17, with the same transcriptional orientation and are distant from less than 7650 base pairs, indicative of an ancestral gene duplication. In humans, the TRPV1 gene spans 17 exons encoding an 839 amino acids (aa) protein. Alternative splicing may occur and give rise to a modified amino acids sequence in the first 150 residues. The TRPV3 gene spans 18 exons encoding a prevalent isoform of 790 amino acids. As for TRPV1, TRPV3 might be differentially spliced, yielding two additional isoforms of 791 (additional A in position 760) and 765 amino acids (peptide sequence at 760–765 modified from DFNKIQ to GTVAVR together with deletion of residues 766–790). The most prevalent forms of TRPV3 (790 aa) and TRPV1 (839 aa) share 43% sequence homology.
2.2 Common features
The TRP superfamily is the second largest class of ions channels with a voltage-dependent activation mechanism. However, TRP members not only respond to electric signal but are also able to sense several environmental stimuli, rendering them polymodal sensors of the environment. These channels share a highly conserved protein architecture and require a tetrameric assembly to generate a functional central cation permeation pore. Apart from this ion channel pore, different subdomains of the TRPV proteins are responsible for their ability to be responsive to various environmental signals. Each subunit of the tetrameric complex is composed of six transmembrane segments (S1–S6), with the cation permeable pore formed by a reentrant loop located between S5 and S6 (Figure 2). The S1–S4 bundle likely forms the voltage sensor module, although TRPV1 and TRPV3 exhibit a weak voltage dependence for gating. This relatively low capacity of TRPV channels to respond to electric current may be due to the scarcity of positively charged amino acids in the S4 domain that contains a single arginine residue [17, 18]. The large cytoplasmic N-terminal part of a monomer comprises six ankyrin repeats, each consisting of a 33-residue motif forming two antiparallel alpha helices separated by loops linking the adjacent repeats. The ankyrin repeat domains (ARDs) are highly conserved in TRPV1 and TRPV3. The C-terminal part is also a large intracellular region containing a TRP-domain, another highly conserved distinctive and fundamental feature of TRP channels, consisting of a 25 amino acids α-helix structure with a conserved sequence IWKLQR called the TRP box. This TRP domain is running parallel to the inner plasma membrane and intimately lodged within the intracellular side of the S1–S4 module [19, 20]. A coiled-coil motif comprising residues of E684–R721 and overlapping with the TRP domain in the C-terminus of TRPV1 has been identified as an association domain and appears to be the molecular determinant of tetramerization . In TRPV3, the C-terminal domain additionally forms a loop of 19 residues from V737 to V756, which has not been observed in other TRPV channels. This unique C-terminal loop domain extends along the TRPV3 intracellular skirt and forms an extensive network of interactions with ankyrin repeats 2–5 of the ARD . Among all of these domains, several regions and specific residues have been mapped within TRPV1 and TRPV3 to regulate the channel gating. Indeed, heat, voltage, and ligand stimuli are sensed by TRPV channels by different structural domains.
2.3 Pore module
Both pores of TRPV1 and TRPV3 are prone to dilatation during stimulation, rendering them permeable for large cations [19, 23]. Thus, TRPV1 and TRPV3 are cation-selective channels exhibiting a notable preference for divalent cations, with the following permeability sequence: Ca2+ > Mg2+ > Na + ≈K+. As for all TRPV channels, negatively charged amino acids in the pore play a central role in cation permeation, and furthermore, the opened pore is blocked by both extra- and intracellular cations. The S5-S6 segments are forming the central pore and the lower gate. This lower gate is formed by a hydrophobic seal, blocking permeation by hydrated ions when the channels are in their closed state. This hydrophobic seal is ensured by the critical residue I679 on S6 for TRPV1 and M677 on S6 for TRPV3 [20, 22]. An additional upper gate is formed by a short loop and helix between S5 and S6, called the pore helix (PH), and acts as a selectivity filter. TRPV1 displays a prolonged loop of 23 residues between S5 and the PH, named the pore turret. This pore turret is a mandatory structural domain for conformational rearrangements during heat activation of the TRPV1 channel, but is not part of the capsaicin agonist activation pathway [24, 25]. In TRPV3, the three key amino acids I644, N647, and Y661 located in the S6 are responsible for heat activation of the channel, since single-point mutants of these generate total loss of temperature activation, without affecting the overall TRPV3 structure . Interestingly, the temperature sensitivity of the TRPV1 channel also implies the C-terminal domain .
TRPV1 can be activated by numerous exogenous agonists including capsaicin, plant toxin resiniferatoxin (RTX), natural substances such as capsaicin-related compounds from peppers, aromatic components, and animal vanillotoxins from the venom of the tarantula [28, 29]. For TRPV1, the three amino acids R491, Y511, and S512 in the S3 transmembrane segment are responsible for capsaicin sensitivity, while the region between S481 and T550 is responsible for binding of the antagonist capsazepine, without affecting the temperature activation [30, 31]. Natural substances also activate TRPV3, including camphor (C612 and C619), carvacrol, thymol, and eugenol . Moreover, TRPV3 can be activated by synthetic molecules such as the well-documented 2-Aminoethoxydiphenyl Borate (2-APB).
2-APB is a common activator ligand of TRPV1 and TRPV3 channels . In TRPV3, several transmembrane segments are implicated in the binding of the agonist 2-APB. In fact, there are three different sites of 2-APB fixation in TRPV3. A first site of fixation is involving S444 of S1, E501 and W493 of S2, and Y565, H523, and F526 of S3 that establish complementary interactions with different atoms of 2-APB . A second site of 2-APB binding is mostly mediated by polar residues, such as H417 and T421 of the linker domain, H426 and H430 of the pre-S1 helix, and R693 and R696 of the TRP domain. Interestingly, the mutation H426A completely abolishes TRPV3 activation by 2-APB but not by camphor neither by carvacrol [22, 33, 34]. However, the residue R696 in the TRP domain appears critical in TRVP3 activation by external ligands since the mutation R696K abolishes 2-APB- and carvacrol-induced calcium influx . The third site of 2-APB fixation is nested in a cavity formed by the extracellular portions of helices S1-S4 and is mediated through both hydrophobic and hydrophilic residues including V458, Y540, R487, and Q483 . The binding of 2-APB on the first two sites described above does not induce gating-associated conformational changes. In opposite, dramatic structural rearrangements are observed when 2-APB binds the third site . Thus, binding of 2-APB to the first two sites is likely a prerequisite for gating, by stabilizing the multiple domains during channel opening.
Endogenous ligands were also reported for TRPV1 and TRPV3: unsaturated N-acyldopamines, lipoxygenase products of arachidonic acid, linoleic acid, Phospholipase C metabolites, and the endocannabinoid anandamide .
In both TRPV1 and TRPV3, the N-terminus module contains a domain able to bind calmodulin (CaM) in a Ca2+-dependent manner . This domain is located between the ankyrin repeats 2 and 3, which comprise a conserved site (K155 and K160 for TRPV1; K169 and K174 for TRPV3) involved in both CaM and ATP binding [37, 38]. In a resting cell, ATP is bound, and the channel is sensitized. Indeed, it has been shown that ATP binding to the TRPV1-ARD generates larger currents in response to capsaicin application [39, 40]. Hence, after channel opening, Ca2+ flows inward and chelates the ATP, which is released from TRPV1-ARD, thus freeing the binding site. In parallel, the Ca2+ influx activates CaM, and Ca2+-CaM can replace the sensitizer and engages the ARD to close the channel . Thus, CaM is involved in Ca2+-dependent desensitization of TRPV1 .
The binding of ATP and Ca2+-CaM to the N-terminal ARD observed in TRPV1 is conserved in TRPV3 , although differences exist. TRPV1 is desensitized after cumulative stimulations. In contrast, TRPV3 is the only member among the TRP channels that sensitizes upon repeated application of stimuli. In addition, the sensitization of TRPV3 is independent of the origin of the stimulus, it will sensitize regardless whether it is activated by heat or chemical ligands. TRPV3 also displays cross-sensitization to stimuli of a different nature, as camphor stimulation causes a sensitization to heat . It is known that sensitization is due to the decrease of the inhibition by calcium from both sides of cells . In the intracellular side, Ca2+-CaM binds ARD and inhibits TRPV3, as described above for TRPV1. The TRPV3-ARD structure is very close to ARD from other members of TRPV channel family, except it exhibits a unique particular conformation of finger 3 loop. This linker region in between the ankyrin repeats 3 and 4 is greatly stabilized by a network of hydrogen bonds and an hydrophobic environment, instead of being flexible as seen in the other TRPV-ARD arrangements . This stabilized finger 3 of TRPV3-ARD may cause steric hindrance, which impedes the binding of CaM. Therefore, CaM binding to ARD probably forces a conformational change of finger 3, thus resulting in an inhibition of TRPV3 function. Upon successive simulations, the finger 3 of TRPV3-ARD undergoes conformational change that decreases the binding of CaM, causing the channel to open more easily. Thus, the finger 3 of TRPV3-ARD functions as a switch in regulation of TRPV3 upon stimulation. Moreover, this distinctive finger 3 segment precedes a conserved threonine 264, which has been identified as a putative site for the ERK1-dependent modulation of TRPV3 . Phosphorylation events could, therefore, alter the conformation of this important loop and powerfully influence the binding of regulatory factors . In others contexts, the influence of phosphorylation events has been demonstrated especially for TRPV1, where phosphorylation of the channel induces sensitization, whereas dephosphorylation is associated to desensitization . The TRPV1 C-terminus also contains modulatory domains able to be phosphorylated and to bind CaM through the 35 amino acids segment E767–T801 [41, 48].
In contrast to TRPV1, the naive TRPV3 channel does not show any intrinsic voltage-dependent activation. The voltage dependence only appears when the TRPV3 channel is primo-stimulated by chemicals or heat stimulus [43, 49]. This voltage dependence of TRPV3 is established by Ca2+ binding on N641 at the pore loop after opening. In addition, the voltage dependence is strongly influenced by Ca2+-CaM binding at the cytoplasmic N terminus. Sensitization is accompanied by a decrease in the voltage dependence. Finally, the sensitized TRPV3 channels are less inhibited than the naive ones, showing faster activation at positive potentials and less deactivation at negative potentials. This gradual shift in Ca2+-dependent regulation or TRPV3 activity is likely related to conformational changes after successive stimulations [43, 44, 46]. Considering the huge complexity in the structural arrangement and interactions of the multiple domains of the TRPV channels, it has been difficult to fully decipher the mechanisms of gating, and many questions remain open.
3. TRPV1 and TRPV3 channels in skin function
3.1 Epidermal barrier function
Ca2+ is well known to contribute to epidermal homeostasis and thus to the formation of an effective skin barrier [50, 51]. In order to maintain its barrier function, the epidermis needs to be renewed every 28 days depending on a calcium gradient. The increase in calcium concentration in the outer layer is essential for the terminal differentiation of keratinocytes, which will lead to the formation of the
The role of TRPV3 in the epidermal differentiation process was highlighted after aberrant expression of early differentiation markers (i.e., KRT1/KRT10) in keratinocytes from
3.2 Sensory modalities in the healthy skin
TRPV1 is a major nonselective cation channel with polymodal mechanisms of activation . Functional TRPV1 serves as a thermal sensor since it is gated by noxious heat greater than 42°C and also chili pepper [9, 55]. The heat nociception was almost abolished following ablation of TRPV1-expressing neurons in mice , but
In contrast to TRPV1, TRPV3 was reported as a warm sensor for innocuous temperatures (approximately 33°C) in different
4. TRPV1 and TRPV3 channels in psoriasis
Psoriasis is a chronic multifactorial inflammatory disease, resulting from the interaction between genetic predisposing factors and environmental triggers, with a global incidence ranging between 0.09% and 5.1% . This dermatosis results from altered signaling between epidermal keratinocytes and the immune system leading to an uncontrolled keratinocyte proliferation (hyperplasia), impaired keratinocyte differentiation (hyperkeratosis), and chronic inflammation. The immune cells (i.e., dendritic and T cells) infiltrating skin lesions produce a wide variety of cytokines (IL-23, IL-17, IFNγ), which activate keratinocytes [66, 67]. Once activated, keratinocytes produce pro-inflammatory cytokines (i.e., IL-6, TNFα), chemokines (i.e., CXCL1, CCL2, CCL13), and antimicrobial peptides (cathelicidin, β-defensine) that further stimulate immune cells and thus maintain the disease in a chronic state. Therefore, keratinocytes not only respond to inflammation but also contribute to the recruitment and the activation of immune cells. Moreover, TRPV1 and TRPV3 channels have a predominant role in inflammation, pain, and pruritus and could be involved in the vicious cycle of the inflammation process in psoriasis.
Indeed, TRPV1 overexpression has been found in the skin of psoriatic patients and in the mouse model of “imiquimod-induced psoriasis” [68, 69]. Imiquimod (IMQ) is a potent immune activator stimulating the IL-23/IL-17 axis and thus mimicking psoriasis inflammation . In 2014, Riol-Blanco
In contrast to TRPV1, TRPV3 channels seem to act on psoriasis from upper cell layers, such as keratinocytes. Indeed, TRPV3 channel expression is increased in psoriatic skin lesions, with significant labeling within the epidermis [68, 75]. Moreover, many studies have supported the role of TRPV3 on inflammation. Upon stimulation, TRPV3 can activate the EGFR/NFκB pathway and induce the release of mediators, such as IL-1α, IL-6, IL-8, TNFα, ATP, and PGE2 [53, 76], which will in turn act on sensory nerves and provoke pain and itching [62, 63]. In addition, Zhao
Altogether, these data support that TRPV1 and TRPV3 are actors of inflammation, either from sensory nerve fibers or from keratinocytes. Both channels seem to have fundamental role in the pathogenesis of psoriasis due to their ability to activate immune cells or to induce cytokine production. It could also be hypothesized that these two channels cooperate during the initiation process of psoriasis.
5. TRPV1 and TRPV3 channels in therapeutic perspectives of psoriasis
The well-known biological strategies to treat an inflammatory disease such as psoriasis consist of using a specific blocking antibody to freeze the interaction of a cytokine with its receptor and then blocking the underlying cytokine-specific biological response. As mentioned earlier, both TRPV1 and TRPV3 are involved in the inflammatory process of psoriasis and could also be potential therapeutic targets in this disease. Indeed, TrkA appears to be a potential target because its inhibition with CT327 blocks the overactivation of TRPV1 on sensory neurons. The discovery of this new molecule is promising since the decrease in pain and pruritus has been observed in psoriatic patients . Interestingly, another study also demonstrated a decrease in skin hyperplasia and erythema in psoriasis murine models treated with the TRPV1 antagonist SB366791 . Research on the inhibition of TRPV1 in psoriasis disease has already emerged and needs to be further explored.
As the TRPV3/TGFα/EGFR signaling complex seems to play a role in psoriasis, EGFR also becomes a potential therapeutic target. A recent clinical study showed that erlotinib, an EGFR inhibitor, significantly decreases hyperkeratosis and pain in Olmsted syndrome patients displaying a TRPV3 overactivation mutation . This highlights that inhibition of EGFR could decrease keratinocytes hyperproliferation/differentiation and might also act on inflammation and pain. Since TRPV3 acts at the first line, directly targeting this channel could also be very promising. Indeed, we reported above some anti-inflammatory molecules, such as 17(R)-resolvin D1, which suppresses TRPV3-induced pain and inflammation. Another potential promising molecule is the TRPV3 antagonist called 74a, which has already proved its efficacy on another inflammatory skin disease .
It could be suggested that inflammatory environment activates TRPV3 from keratinocytes and TRPV1+ nerves for the induction of pain, itching, and inflammation. The cooperation of these two channels, with the potential activation of TRPV1 induced by downstream mediators of TRPV3, cannot be excluded. To increase further the complexity of the TRPV1 and TRPV3 relationship, it has been demonstrated that TRPV1 and TRPV3 could form interacting partners, therefore assembling heterochannels [84, 85]. The biological significance of these heterochannels is still not known, but this could be involved in a very fine-tuning of sensitivity. In addtion, a recent study showed that the intergenic region between TRPV1 and TRPV3 coding sequences contained a human specific transposable element (SVA: SINE-VNTR-Alu retrotransposon) insertion, located upstream of the TRPV3 promoter and downstream of the 3′ end of TRPV1 . This SVA insertion acts as a cis-regulatory element allowing coexpression of TRPV1 and TRPV3 in multiple human tissues, which is not observed in mice. Thus, targeting these two channels simultaneously could be a very promising approach for the treatment of psoriasis in human.
TRPV1 and TRPV3 are important channels for maintaining the skin homeostasis and its function. A deregulation of their expression and/or activity is associated to the establishment of an inflammatory response. Several studies already demonstrated their contribution in psoriasis by highlighting their capacities to activate typical inflammatory pathways (IL-23/IL-17 axis, NF-κB pathway) and/or to provoke the release of inflammatory mediators. It would therefore be interesting to explore the exact contribution of TRPV1 and TRPV3 in the psoriasis typical chronic skin inflammation: are they the trigger or are they one of the multiple factors involved in maintaining inflammation?
It would be interesting to explore the presence of TRPV1 and TRPV3 in other tissues of the body subjected to chronic inflammation, such as the intestinal epithelium. The future challenge will be to develop specific compounds that target the TRPV1/TRPV3 to limit chronic inflammation without affecting their physiological functions.
Conflict of interest
The authors declare no conflict of interest.
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