Is TRPV3 a Drug Target?—A Decade of Learning

Chapter 11


Is TRPV3 a Drug Target?—A Decade of Learning



Neelima Khairatkar Joshi*    Glenmark Research Centre, Navi Mumbai, Glenmark Pharmaceuticals Ltd, India
* Corresponding author: neelima_joshi@glenmarkpharma.com



Abstract


Transient receptor potential cation channel, subfamily V, member 3 (TRPV3) channel was identified as a molecular sensor of “warm to hot” temperatures almost a decade ago (Xu et al., 2002; Smith et al., 2002; Peier et al., 2002 [13]). Subsequently, based on its neuronal up-regulation in pain states, it was recognized as a promising target in novel analgesic development (Facer et al., 2007; Bevan et al., 2008 [10,40]). TRPV3 channel has been under continued research since then, albeit not as aggressively as few other TRP channels. Nevertheless, learning from the recent efforts has further revealed its intriguing role in hair and skin homeostasis, cutaneous sensory responses, and potential role in skin diseases. Recent recognition of its gain-of-function mutation in mice and humans clearly takes the scope of TRPV3 blockade beyond pain sensory pathways to attenuating hyperkeratotic, inflammatory skin disorders accompanied with itch and/or pain (Imura et al., 2009; Yoshika et al., 2009; Lin et al., 2009 [3335]). This chapter gives recent insights into the therapeutic potential of TRPV3 blockade in multiple diseases with unmet medical needs including chronic pain conditions and skin diseases.



Introduction


Cloning of the TRPV3 channel gene was simultaneously reported by three independent laboratories. Human TRPV3 gene was cloned from the human testes library during database searches for TRP-related Expressed Sequence Tags (ESTs) by one group and during homology searches for the TRPV1-like gene of the Celera Human and public databases by another group [1,2]. Murine TRPV3 gene was cloned from the skin of a newborn mouse almost simultaneously [3]. TRPV3 channel protein has a prototype TRP structure with six transmembrane domains, a pore-loop region between the last two membrane-spanning domains, and three predicted ankyrin domains. The TRPV3 channel has low identity of ~ 43%, 42%, 41%, and 30% to TRPV1, TRPV4, TRPV2, and TRPV5 and TRPV6 channels, respectively [2]. Recent insights into structural and biophysical features are beyond the scope of this chapter, and interested readers can refer to Refs. [4,5].


TRPV3 Tissue Expression


TRPV3 shows neuronal and nonneuronal expression in humans and mice. Although initial studies did not demonstrate TRPV3 expression in rodent dorsal root ganglia (DRG) neurons [3,6], subsequently its expression on human and rodent DRG, trigeminal, hippocampal, and superior cervical neurons and peripheral nerve endings and rat brain was convincingly shown [1,2,710]. In the brain, TRPV3 is expressed in ventral motor neurons, superior cervical ganglion neurons, deeper laminae of dorsal horn, and nigral dopaminergic neurons, although its physiological role in these areas remains to be investigated.


There is ample evidence that TRPV3 channel is expressed in skin keratinocytes in man [1,2] and mice [3,6,1113]. It is abundantly expressed in differentiated basal layer cells and undifferentiated suprabasal layers of mouse epidermis, suggesting a role in cutaneous thermosensation [1416]. Heat-induced TRPV3 signals are believed to be transferred from keratinocytes to nearby free nerve endings in the dermis, thereby causing sensation of warmth or heat. Although no synapses are found between keratinocytes and sensory termini, it is possible that they transduce signals to surrounding nerves through chemical mediators. Its physiological role in skin barrier formation, hair growth, and cutaneous growth and survival is recently reviewed in depth elsewhere [4].


Apart from the skin, TRPV3 is also expressed in nasal and oral cavity, mainly in the tongue and palate [13]. In the mouth, TRPV3-like immunoreactivity is restricted to epithelial layers facing oral cavity. Its presence in the tongue and palate implies its function as a target for flavor actions of several plant-derived derivatives such as carvacrol and eugenol.


TRPV3 Activation


The mammalian nervous system detects temperature over a wide range, extending from noxious cold to noxious hot. Miscellaneous ThermoTRPs are implicated in this thermosensory function. TRPV1, TRPV2, TRPV3, and TRPV4 are responsible for warm to hot temperature sensing [16]. TRPV3 is activated by innocuous warmth (31-39 °C), which is further maintained at higher noxious temperatures. Specific structural domains involved in this are yet to be determined but could be associated with the TRP box region at C terminal as seen with some other thermoTRPs.


TRPV3 channel can be alternatively activated by nonthermal stimuli as well. A variety of nonselective natural compounds such as camphor, menthol, carvacrol, and eugenol have been recognized as TRPV3 activators [6,13]. Camphor is a plant-derived monoterpene, a weak agonist of TRPV3 channel and known to sensitize human skin to warm temperatures [13]. A recent study has demonstrated that the cysteine residues at the pore region of the channel play a critical role in its camphor sensitivity [17]. Menthol is a monoterpene-based partial agonist of TRPV3 channel and shows much less (~ 65%) activation of the channel compared to that by camphor. Paradoxically, in humans, camphor and menthol exhibit the opposite thermal sensation of feeling warm and cool, respectively. The reason for this is not completely understood but could be due to nonselective and concentration dependent activation of other TRP channels by these agents.


Carvacrol and eugenol are major ingredients of oregano and clove, respectively, and are nonselective activators of TRPV3 [13]. Overall, TRPV3 activation by these pungent, plant-derived chemicals implies a central role for TRPV3 in the protective, chemosensory mechanisms of skin. 2-Aminoethoxydiphenyl borate (2-APB) was first identified as a synthetic, nonterpenoid agonist of the TRPV3 channel. Although it is a widely used TRPV3 agonist in majority of investigations, caution should be exercised in interpreting the results because it is known to be a nonselective agent with simultaneous action on receptors other than TRPV3 as reviewed earlier [18]. The 2-APB activation of TRPV3 was very recently demonstrated to depend on presence of two residues H426 and R696 in the cytoplasmic region of channel and is separable from camphor or voltage response in human, dog, and frog [19]. Another recently described TRPV3 agonist is incensol acetate, a constituent of Boswellia cerrata resin [20]. However, its nociceptive properties remain to be described.


Various agonists listed earlier are shown to reduce the heat activation threshold of TRPV3. Despite recognition of several exogenous activators as listed earlier, a specific and selective TRPV3 channel agonist with nociceptive properties is yet to be identified.


Several endogenous biochemical mediators are also identified as TRPV3 sensitizers and activators. These are mainly produced during tissue injury or inflammation, and they include protein kinase C (PKC), nitric oxide (NO), and n-6 unsaturated fatty acids, in particular arachidonic acid (AA) as reviewed earlier [18]. Activation of PKC in skin cells and sensory neurons is an important event downstream of pro-inflammatory receptor activation. NO is one of the important and pleiotropic cell-signaling molecules that modulate diverse biological processes during inflammation and injury. NO-mediated signaling occurs via S-nitrosylation of TRP channel proteins as a posttranslational modification [21]. The TRPV3 channel belongs to a new category of cell surface receptors that can integrate NO and Ca2 + signals. Phospholipase C-coupled, G-protein coupled receptors (GPCRs) such as histamine and bradykinin may potentiate TRPV3 function under inflammatory conditions when these are produced and released in mass amounts. The TRPV3 channel could have an important role during inflammation as an integrator of signals from GPCRs at the level of neuronal input further to the PNS and CNS. Hence TRPV3 might be involved in the initiation and maintenance of sensory hypersensitivity during tissue inflammation.


Arachidonic acid-mediated potentiation of the TRPV3 channel appears very interesting as it seems to be highly specific for TRPV3 because TRPV1, TRPV2, and TRPV4 are not activated by AA, and other saturated fatty acids are devoid of this effect [22]. Arachidonic acid is an endogenous mediator of inflammatory response in skin cells. It is released into extracellular milieu by infiltrating lymphocytes. In severe cases of “involved psoriasis,” AA concentration in the epidermis reaches very high levels, close to the concentration at which it shows robust TRPV3 potentiation under in vitro conditions [23,24]. Even under less severe conditions, the combined concentrations of free unsaturated fatty acids are likely to be sufficient to achieve TRPV3 activation. Moreover the in vitro studies demonstrate that TRPV3 activating effects of AA seem to increase with longer incubation. Hence AA seems to be a pathologically most relevant means for TRPV3 channel activation during skin inflammation. Overabundance of AA is also found in patients with osteoarthritis. A recently published clinical trial shows association of AA with synovitis in the osteoarthritic (OA) knee [25]. High levels of (n-6) fatty acids in cancellous bone in osteoarthritis are also reported [26].


The TRPV3 channel has a unique mode of activation among thermoTRPs in that it is continuously sensitized on repeated agonist application [1,3,12,27]. This is in contrast to other structurally and functionally related TRP channels (such as TRPV1, TRPV4, and TRPA1), which are desensitized under such conditions. This feature has been observed both with recombinant TRPV3 and native TRPV3 on keratinocytes and is stimulus independent seen with all TRPV3 agonists [12]. The actual sensitization of TRPV3 channel is believed to involve relief from Ca2 +-mediated inhibition of channel function [27].


Functional Role of TRPV3 Channel: Evidence from Genetic Studies


TRPV3 global knockout mice, as well as mice overexpressing TRPV3 in keratinocyte specific fashion, confirm role of TRPV3 in thermosensation and nociceptive signaling pathway [6,28]. This has been discussed in details earlier by us [18].


TRPV3 and Human Diseases


The TRPV3 channel has a well-defined tissue distribution [6]. Its presence in peripheral nerves and its abundance in skin keratinocytes imply a pivotal role for TRPV3 in sensory pathways involved in pain and inflammatory skin diseases. Its confirmed role in thermal nociception and its implicated role in pain and cutaneous signaling following peripheral nerve activation and/or injury is amply discussed elsewhere [4,10,15,2830].


Skin Diseases


TRPV3 activation on keratinocytes may lead to the release of endogenous substances that, in turn, activate adjacent cutaneous sensory nerve terminals. A number of candidate mediators of pathological nature such as prostaglandin E2 (PGE2), ATP, increased intracellular Ca2 +, and IL-1α are released by activated TRPV3 on keratinocytes [13,15,28]. Keratinocytes cultured from TRPV3 overexpressing animals showed augmented TRPV3 ion channel activity and increased PGE2 mediator release in a gene-dosage dependent manner and in response to 2-APB, camphor, or heat [28]. TRPV3-dependant PGE2 release from keratinocytes may contribute to sensory functions, including acute nociception and hyperalgesia via the Prostaglandin E receptor (EP) receptor activation. TRPV3-dependant IL-1α release may have special importance because IL-1α is an important mediator of cutaneous inflammation. Release of IL-1 from keratinocytes in a TRPV3-dependant manner also supports the involvement of TRPV3 in the development of psoriasis [13]. Some of the antipsoriatic drugs such as hydrocortisone and 2-OH vitamin D3 work through IL-1 release inhibition [31]. Itch is an inflammatory and sensory response wherein cutaneous epidermal cells and neurites play a major role, and TRPV3 is expressed on both.


There is ample evidence from TRPV3 gain-of-function (GOF) mutations in mice (as well as in humans) that support the hypothesized role of the TRPV3 channel in itchy skin diseases. The TRPV3 Gly573Ser GOF in TRPV3 is found to cause itchy dermatitis in rodents [32,33]. Another study on transgenic Nh mice overexpressing mutated TRPV3 channels showed enhanced release of nerve growth factor (NGF), a powerful sensitizer of sensory neurons, from epidermal sheets [34]. Further, the same GOF mutation is recently reported in human TRPV3 and was found to steer the skin to a hyperkeratotic itchy cutaneous condition, called Olmstead syndrome [35]. In atopic dermatitis patients, increased sprouting of epidermal C fibers is seen, inducing hypersensitivity to itching, which aggravates the disease, and this is accompanied by higher expressions of TRPV3 mRNA [29,36].


The postulated role of TRPV3 in skin-nerve cross talk and in modulating cutaneous hypersensitivity in inflammatory dermatoses such as itchy dermatitis and psoriasis is further strengthened by the fact (although histamine is the best-known pruritogen and a main target for antipruritic therapies) that histamine H1 receptor (H1R) antagonists are often ineffective in certain pruritic skin conditions, including dry skin pruritus [37]. There is increasing belief that miscellaneous inflammatory mediators other than histamine could have a key role in itching. Some of the newly recognized putative pruritogens, as depicted in Figure 11.1, are indeed activators of TRPV3 implicating its role in histamine-resistant itch.


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Figure 11.1 TRPV3-mediated cutaneous signaling between keratinocyte TRPV3 and nearby TRPV3 on free nerve endings via chemical mediators or enhanced TRPV3 activity due to gain-of-function mutation resulting in itchy skin disease condition [38].

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Nov 18, 2017 | Posted by in PHARMACY | Comments Off on Is TRPV3 a Drug Target?—A Decade of Learning
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