Chapter 27

Conclusions

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.

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 [2–4] 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 http://clinicaltrials.gov/ct2/show/NCT01556152) 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 [11–13]. 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) [17–19]. 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 [21–25].

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.