Chapter 27


Magdalene Moran*    Hydra Biosciences Cambridge, MA, USA
* Corresponding author:

As you have read, it is a very exciting time for transient receptor potential (TRP) research. Studies involving TRPs continue to proliferate; a recent PubMed search on TRP channels uncovered over 1000 papers published in 2013 alone (see Figure 27.1). With this continuing surge in research, the diversity in TRP channel function becomes even more apparent, and we find we can make fewer generalizations about this superfamily. These fascinating cation channels are involved in multiple cellular processes and contribute to numerous disease states. Hopefully our increasing knowledge about TRP channel function will translate into new medicines that will address underserved patient populations. So far, few TRP channel modulators have been used clinically; the true clinical value of the TRPs remains to be determined.


Figure 27.1 Number of TRP publications in pubmed by year (1994–2013)

TRPV1 remains the best-studied family member. Both agonists and antagonists of TRPV1 have been tested in human clinical trials. Although the TRPV1 antagonists have thus far been plagued with issues of impaired thermoregulation and thermosensation that remain to be overcome, TRPV1 agonists have been shown to be efficacious analgesics. Topical capsaicin rubs remain popular, and the Qutenza patch received FDA approval for the treatment of postherpetic neuralgia [1]. In addition, intrathecal and intravesicular TRPV1 agonists also show promise in cancer pain and bladder disorders.

Significant excitement also surrounds TRPA1. TRPA1 antagonists show efficacy in multiple preclinical models of both inflammatory [24] and peripheral neuropathic pain. Recent discoveries in models of painful diabetic [5,6] and chemotherapy-induced peripheral neuropathies [7,8] suggest that TRPA1 antagonists might be able to prevent damage in addition to reducing pain [5,7,8]. A trial of a TRPA1 antagonist in painful diabetic neuropathy (Glenmark, see recently completed. According to a Glenmark press release, in a double-blind, placebo controlled trial of 138 patients in Europe and India, GRC 17536 demonstrated a statistically and clinically significant pain reduction in a pre-specified subgroup of patients with moderate to severe pain due to diabetic neuropathy. Clinical trials in chronic cough and asthma are also underway, highlighting the excitement around recent discoveries of a role for TRPA1 in the pulmonary field.

TRPV4 is also a potentially interesting pulmonary target. Single nucleotide polymorphisms in TRPV4 are associated with airflow obstruction in chronic obstructive pulmonary disease (COPD) patients [9]. ex vivo studies on the human bronchus suggest that TRPV4 activation leads to bronchiole constriction that is dependent on cysteine leukotrienes [10]. Studies in laboratory animals from multiple groups also implicate TRPV4 in both cardiogenic and noncardiogenic pulmonary edema [1113]. Antagonizing murine TRPV4 reduces pulmonary edema and improves arterial oxygen tension after aortic banding [12]. Similarly, blocking TRPV4 in mice attenuates edema after myocardial infarction [12].

TRPV4 is one of several TRP channels implicated in metabolic syndromes. Inhibition of TRPV4 increases markers of brown fat in cultured adipocytes and increases glucose tolerance in mice [14]. Similarly, the cold-activated channel, TRPM8, has been found in brown fat. Activation of TRPM8 with menthol increases brown adipose tissue thermogenesis and reduces dietary obesity in mice [15]. In addition to their potential role in brown fat, TRPs, including TRPM5 and TRPV1, have also been implicated in diabetes [16].

One of the most intriguing areas of recent TRP channels research has been in dermatology. Both TRPA1 and TRPV1 have been shown to play significant roles in pruritus (itch) [1719]. Genetic deletion or pharmacological inhibition of TRPA1 also attenuates the severity of atopic dermatitis symptoms in a murine model [20]. In addition, human and rodent genetic data implicate overactive TRPV3 in keratinocyte dysfunction and itch [2125].

Mutations in TRP channels lead to a variety of heritable disorders. These include skeletal dysplasias and neuropathies (TRPV4) [26], kidney diseases (TRPC6) [27], mucolipidosis type IV (TRPML1) [28,29], dermatologic disorders (TRPV3) [23], and pain syndromes (TRPA1) [30]. Most, though not all, of the disease-causing mutations appear to be gain-of-function mutations that lead to channel hyperexcitability and subsequent toxicity. In addition, polymorphisms in TRP channels have also been associated with susceptibility to disease. For example, TRPV1 polymorphisms have been associated with multiple pathologies including cough [31], migraine [32], and type I diabetes [33]. Most recently, epigenetic studies revealed a potential link between heat pain sensitivity and methylation of the TRPA1 promoter [34], though the significance of this remains to be determined.

As TRPs are implicated in more disease states and the pace of research accelerates, questions regarding the clinical utility of TRP channel modulators take center stage. With any new mechanism one wonders whether preclinical efficacy will translate into humans. Which will be a more fruitful approach—agonizing a channel to induce a persistent desensitization or antagonizing it? Will it depend on the channel? Are TRP channels performing functions we have yet to appreciate that will impact the tolerability of modulators? Although speculation is rampant, data remains scarce. As in the preclinical arena, the inherent diversity of TRP channel structure and function will make it difficult to generalize about the family from early results, and each mechanism will require independent testing. In the next few years, clinical studies involving a number of mechanisms should help us answer these questions. Meanwhile, the rapidly emerging stories around TRP channels make us optimistic that this diverse superfamily will yield useful therapies for human disease.


[1] Moran MM, McAlexander MA, Biro T, Szallasi A. Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov. 2011;10(8):601–620.

[2] Eid SR, Crown ED, Moore EL, Liang HA, Choong KC, Dima S, et al. HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol Pain. 2008;4:48.

[3] del Camino D, Murphy S, Heiry M, Barrett LB, Earley TJ, Cook CA, et al. TRPA1 contributes to cold hypersensitivity. J Neurosci. 2010;30(45):15165–15174.

[4] Chen J, Joshi SK, DiDomenico S, Perner RJ, Mikusa JP, Gauvin DM, et al. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation. Pain. 2011;152(5):1165–1172.

[5] Koivisto A, Hukkanen M, Saarnilehto M, Chapman H, Kuokkanen K, Wei H, et al. Inhibiting TRPA1 ion channel reduces loss of cutaneous nerve fiber function in diabetic animals: sustained activation of the TRPA1 channel contributes to the pathogenesis of peripheral diabetic neuropathy. Pharmacol Res. 2012;65(1):149–158.

[6] Wei H, Hamalainen MM, Saarnilehto M, Koivisto A, Pertovaara A. Attenuation of mechanical hypersensitivity by an antagonist of the TRPA1 ion channel in diabetic animals. Anesthesiology. 2009;111(1):147–154.

[7] Nassini R, Gees M, Harrison S, De Siena G, Materazzi S, Moretto N, et al. Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain. 2011;152(7):1621–1631.

[8] Trevisan G, Materazzi S, Fusi C, Altomare A, Aldini G, Lodovici M, et al. Novel therapeutic strategy to prevent chemotherapy-induced persistent sensory neuropathy by TRPA1 blockade. Cancer Res. 2013;73(10):3120–3131.

[9] Zhu G, Gulsvik A, Bakke P, Ghatta S, Anderson W, Lomas DA, et al. Association of TRPV4 gene polymorphisms with chronic obstructive pulmonary disease. Hum Mol Genet. 2009;18(11):2053–2062.

[10] McAlexander MA, Luttman MA, Hunsberger GE, Undem BJ. Transient receptor potential vanilloid 4 (TRPV4) activation constricts the human bronchus via the release of cysteinyl leukotrienes. J Pharmacol Exp Ther. 2014;349(1):118–125.

[11] Hamanaka K, Jian MY, Weber DS, Alvarez DF, Townsley MI, Al-Mehdi AB, et al. TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs. Am J Physiol Lung Cell Mol Physiol. 2007;293(4):L923–L932.

[12] Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY, et al. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med. 2012;4(159):159ra48.

[13] Yin J, Hoffmann J, Kaestle SM, Neye N, Wang L, Baeurle J, et al. Negative-feedback loop attenuates hydrostatic lung edema via a cGMP-dependent regulation of transient receptor potential vanilloid 4. Circ Res. 2008;102(8):966–974.

[14] Ye L, Kleiner S, Wu J, Sah R, Gupta RK, Banks AS, et al. TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell. 2012;151(1):96–110.

[15] Ma S, Yu H, Zhao Z, Luo Z, Chen J, Ni Y, et al. Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. J Mol Cell Biol. 2012;4(2):88–96.

[16] Uchida K, Tominaga M. The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion. Endocr J. 2011;58(12):1021–1028.

[17] Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X, et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci. 2011;14(5):595–602.

[18] Wilson SR, Nelson AM, Batia L, Morita T, Estandian D, Owens DM, et al. The ion channel TRPA1 is required for chronic itch. J Neurosci. 2013;33(22):9283–9294.

[19] Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI, Basbaum AI, et al. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci USA. 2009;106(27):11330–11335.

[20] Liu B, Escalera J, Balakrishna S, Fan L, Caceres AI, Robinson E, et al. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J. 2013;27(9):3549–3563.

[21] Duchatelet S, Pruvost S, de Veer S, Fraitag S, Nitschke P, Bole-Feysot C, et al. A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia. JAMA Dermatol. 2014;150(3):303–306.

[22] Eytan O, Fuchs-Telem D, Mevorach B, Indelman M, Bergman R, Sarig O, et al. Olmsted syndrome caused by a homozygous recessive mutation in TRPV3. J Invest Dermatol. 2014;134(6):1752–1754.

[23] Lin Z, Chen Q, Lee M, Cao X, Zhang J, Ma D, et al. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. Am J Hum Genet. 2012;90(3):558–564.

[24] Yamamoto-Kasai E, Imura K, Yasui K, Shichijou M, Oshima I, Hirasawa T, et al. TRPV3 as a therapeutic target for itch. J Invest Dermatol. 2012;132(8):2109–2112.

[25] Yoshioka T, Imura K, Asakawa M, Suzuki M, Oshima I, Hirasawa T, et al. Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice. J Invest Dermatol. 2009;129(3):714–722.

[26] Cho TJ, Matsumoto K, Fano V, Dai J, Kim OH, Chae JH, et al. TRPV4-pathy manifesting both skeletal dysplasia and peripheral neuropathy: a report of three patients. Am J Med Genet A. 2012;158A(4):795–802.

[27] Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308(5729):1801–1804.

[28] Sun M, Goldin E, Stahl S, Falardeau JL, Kennedy JC, Acierno Jr. JS, et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet. 2000;9(17):2471–2478.

[29] Bassi MT, Manzoni M, Monti E, Pizzo MT, Ballabio A, Borsani G. Cloning of the gene encoding a novel integral membrane protein, mucolipidin-and identification of the two major founder mutations causing mucolipidosis type IV. Am J Hum Genet. 2000;67(5):1110–1120.

[30] Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S, et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron. 2010;66(5):671–680.

[31] Smit LA, Kogevinas M, Anto JM, Bouzigon E, Gonzalez JR, Le Moual N, et al. Transient receptor potential genes, smoking, occupational exposures and cough in adults. Respir Res. 2012;13:26.

[32] Carreno O, Corominas R, Fernandez-Morales J, Camina M, Sobrido MJ, Fernandez-Fernandez JM, et al. SNP variants within the vanilloid TRPV1 and TRPV3 receptor genes are associated with migraine in the Spanish population. Am J Med Genet Part B. 2012;159B(1):94–103.

[33] Sadeh M, Glazer B, Landau Z, Wainstein J, Bezaleli T, Dabby R, et al. Association of the M3151 variant in the transient receptor potential vanilloid receptor-1 (TRPV1) gene with type 1 diabetes in an Ashkenazi Jewish population. IMAJ, Isr Med Assoc J. 2013;15(9):477–480.

[34] Bell JT, Loomis AK, Butcher LM, Gao F, Zhang B, Hyde CL, et al. Differential methylation of the TRPA1 promoter in pain sensitivity. Nat Commun. 2014;5:2978.

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Nov 18, 2017 | Posted by in PHARMACY | Comments Off on Conclusions

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