The Role of Transient Receptor Potential Vanilloid 1 in Common Diseases of the Digestive Tract and the Cardiovascular and Respiratory System
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Transient receptor potential vanilloid subtype 1 (TRPV1), a member of the transient receptor potential vanilloid (TRPV) channel family, is a non-selective cation channel and that is widely expressed in sensory nerve fibers and nonneuronal cells, including certain vascular endothelial cells and smooth muscle cells. The activation of TRPV1 may be involved in the regulation of various physiological functions, such as the release of inflammatory mediators in the body, gastrointestinal motility function, and temperature regulation. In recent years, a large number of studies have revealed that TRPV1 plays an important role in the physiological and pathological conditions of the digestive system, cardiovascular system, and respiratory system, but there is no systematic report of TRPV1.The objective of this review is to explain the function and affection of TRPV1 in specific diseases, such as irritable bowel syndrome, hypertension, and asthma, and further investigates the intrinsic relationship between the expression and function of TRPV1 in those diseases, in order to find new therapeutic targets for the cure of related diseases.Keywords:
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In this issue of the BJUI, Charrua et al. 1 report on the possible interaction of two members of the vanilloid subfamily of transient receptor potential (TRP) channels in the control of rat urinary bladder function, TRPV1 and TRPV4. TRP channels are a family of cation-selective channels with 28 known mammalian members. Six of them belong to the subfamily of vanilloid receptors (TRPV channels) and fall into four groups, TRPV1/TRPV2, TRPV3, TRPV4, and TRPV5/TRPV6. The physiological and pharmacological interest in these channels results largely from the finding that they can be activated by a plethora of physical and chemical stimuli; accordingly, they have been implicated in sensory function and pathophysiology of many organ systems 2. A breakthrough in our understanding of such channels came with the reporting of TRPV1 and TRPV4 knock-out mice, which also exhibit a bladder phenotype; the role of TRP channels in lower urinary tract function has comprehensively been reviewed recently 3. While the physiological regulation of TRPV1 by endogenous mediators is poorly understood, natural compounds such as capsaicin or resiniferatoxin are acute agonists of TRPV1 channels; however, over time, they desensitise the channel and hence act as inhibitors. These compounds have shown promise in the treatment of detrusor overactivity but also have problems attributed to their initial agonist effects 3. TRPV4 are activated experimentally by hypotonicity induced cell swelling and several chemicals and more physiologically by moderate heat, stretch and shear stress, leading to the proposition that they may functions as a stretch sensor in the bladder. The inhibitory effects of TRPV1 agonists manifest only after prolonged exposure once desensitisation of their agonist effects occurs, and this initial agonistic phase is a source of undesirable effects. Therefore, a search is on for small molecules that have direct antagonist effects. Charrua et al. 1 now report that two small molecule antagonists at TRPV1 and TRPV4, (SB355791 and RN1734, respectively) even in high doses did not affect bladder function in control rats. Intravesical installation of lipopolysaccharide is used to create an animal model of cystitis as it induces inflammation, detrusor overactivity and bladder pain. In this model, a high dose of the TRPV4 inhibitor reduced detrusor overactivity, whereas even the high dose of the TRPV1 inhibitor did not; however, a combination of ineffective doses of both inhibitors markedly decreased bladder reflex activity. On the other hand, each of the two drugs caused partial analgesia, but their combination was not more effective than either drug alone. This indicates an interesting functional interaction between TRPV1 and TRPV4 channels, which is specific for the overactivity vs the pain response. Previously, the Cruz group reported that bladder overactivity induced by nerve growth factor depends on the presence of functionally active TRPV1 4. Taken together this work shines light on networks of multiple mediators and their receptors that cooperate in the regulation of bladder function but previously have mainly been viewed in isolation. Such work may also have therapeutic consequences. As target-saturating concentrations of ligands at any of these receptors may cause relevant adverse effects, targeting multiple such receptors in low doses may open an avenue for a multi-pronged approach, particularly in patients with bladder dysfunction difficult to control with present treatment options. This multiple target, low-dose approach is a therapeutically fascinating idea, but finding the right combination of doses in such a setting is a nightmare for any drug development scientist. Moreover, much of the specific role of such targets in pathophysiology remains to be explored before the present findings can be translated into clinical treatments, and the Charrua et al. study 1 will also help such efforts in other ways. Some of the initial thinking on the function of TRP channels in the control of bladder and other functions has been based on localisation studies with TRP channel antibodies, which may have been flawed. Similar to many other receptor antibodies 5, several of those directed against TRPV1 channels also have been shown to lack target specificity 6, leading to misunderstandings about the location and function of such channels. The validation for other TRPV1 and TRPV4 antibodies presented by Charrua et al. 1 will allow more robust studies in this regard and help to develop more valid understanding of TRP channels in physiology, pathophysiology and as treatment targets. The author currently is an employee of Boehringer Ingelheim.
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Noxious thermal, mechanical, or chemical stimuli evoke pain through excitation of the peripheral terminals called nociceptor, and many kinds of ionotropic and metabotropic receptors are involved in this process. Capsaicin receptor TRPV1 is a nociceptor-spesific ion channel that serves as the molecular target of capsaicin. TRPV1 can be activated not only by capsaicin but also by noxious heat (with a thermal threshold > 43°C) or protons (acidification), all of which are known to cause pain in vivo. Studies using TRPV1-deficient mice have shown that TRPV1 is essential for selective modalities of pain sensation and for thermal hyperalgesia. One mechanism underlying inflammatory pain which is initiated by tissue damage / inflammation and characterized by hypersensitivity is sensitization of TRPV1. In addition to TRPV1, there are five thermosensitive ion channels in mammals, all of which belong to the TRP (transient receptor potential) super family. These include TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1. These channels exhibit distinct thermal activation thresholds ( > 52°C for TRPV2, > ∼34-38°C for TRPV3, > ∼27-35°C for TRPV4, < ∼25-28°C for TRPM8 and < 17°C for TRPA1) and are expressed in primary sensory neurons as well as other tissues. Some of the thermosensitive TRP channels are likely to be involved in thermal nociception, since their activation thresholds are within the noxious range of temperatures. Keywords: trp channel, pain, capsaicin, nociception, thermosensation
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Transient receptor potential vanilloid subtype 1 (TRPV1), a member of the transient receptor potential vanilloid (TRPV) channel family, is a non-selective cation channel and that is widely expressed in sensory nerve fibers and nonneuronal cells, including certain vascular endothelial cells and smooth muscle cells. The activation of TRPV1 may be involved in the regulation of various physiological functions, such as the release of inflammatory mediators in the body, gastrointestinal motility function, and temperature regulation. In recent years, a large number of studies have revealed that TRPV1 plays an important role in the physiological and pathological conditions of the digestive system, cardiovascular system, and respiratory system, but there is no systematic report of TRPV1.The objective of this review is to explain the function and affection of TRPV1 in specific diseases, such as irritable bowel syndrome, hypertension, and asthma, and further investigates the intrinsic relationship between the expression and function of TRPV1 in those diseases, in order to find new therapeutic targets for the cure of related diseases.
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Abstract We feel a wide range of temperatures spanning from cold to heat. Within this range, temperatures over about 43°C and below about 15°C evoke not only a thermal sensation, but also a feeling of pain. In mammals, six thermosensitive ion channels have been reported, all of which belong to the TRP (transient receptor potential) superfamily. These include TRPV1 (VR1), TRPV2 (VRL‐1), TRPV3, TRPV4, TRPM8 (CMR1), and TRPA1 (ANKTM1). These channels exhibit distinct thermal activation thresholds (>43°C for TRPV1, >52°C for TRPV2, >∼34–38°C for TRPV3, >∼27–35°C for TRPV4, <∼25–28°C for TRPM8 and <17°C for TRPA1), and are expressed in primary sensory neurons as well as other tissues. The involvement of TRPV1 in thermal nociception has been demonstrated by multiple methods, including the analysis of TRPV1‐deficient mice. TRPV2, TRPM8, and TRPA1 are also very likely to be involved in thermal nociception, because their activation thresholds are within the noxious range of temperatures. © 2004 Wiley Periodicals, Inc. J Neurobiol 61: 3–12, 2004
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Acupuncture is a common complementary and alternative therapy around the world, but its mechanism remains still unclear. In the past decade, some studies indicated that transient receptor potential vanilloid (TRPV) channels play a great role in the response of acupuncture stimulation. In this article, we discussed the relationship between acupuncture and TRPV channels. Different from inhibitors and agonists, the regulation of acupuncture on TRPV channels is multi-targeted and biphasic control. Acupuncture stimulation shows significant modulation on TRPV1 and TRPV4 at the autonomic nervous system (ANS) including central and peripheral nervous systems. On the contrary, the abundant expression and functional participation of TRPV1 and TRPV4 were specific to acupuncture stimulation at acupoints. The enhancement or inhibition of TRPV channels at different anatomical levels will affect the therapeutic effect of acupuncture. In conclusion, TRPV channels help to understand the principle of acupuncture stimulation, and acupuncture also provides a potential approach to TRPV-related trials.
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日本に暮らす私たちは1年を通して四季折々様々な温度を感じて過ごしており，さらに，約43度以上と約15度以下は温度感覚に加えて痛みをもたらすと考えられている．私たちはそれらの温度を感じ，意識的・無意識的にそれに対応して熱の喪失や産生等を行っている．外界の温度受容の場合，末梢感覚神経が温度刺激を電気信号（活動電位）に変換してその情報が中枢へと伝達されると考えられているが，温度受容に関わる分子として，哺乳類では6つのTRPチャネル；TRPV1（VR1），TRPV2（VRL-1），TRPV3，TRPV4，TRPM8（CMR1），TRPA1（ANKTM1）が知られており，それぞれに活性化温度閾値が存在する（TRPV1＞43度，TRPV2＞52度，TRPV3＞32－39度，TRPV4＞27－35度，TRPM8＜25－28度，TRPA1＜17度）．TRPV1，TRPV4とTRPM8は，その活性化温度閾値が一定でなく変化しうる．TRPV1の活性化温度閾値は代謝型受容体との機能連関によって30度近くまで低下し，体温が活性化刺激となって痛みを惹起しうる．これらの温度感受性TRPチャネルは感覚神経に多く発現しているが，皮膚表皮細胞等ほかの部位に発現しているものもある．この6つの温度感受性TRPチャネルのうち，TRPV1，TRPV2，TRPA1は温度刺激による痛み受容にも関与していると思われる．身近でありながらほとんど明らかでなかった温度受容のメカニズムが受容体分子の発見ととも明らかになりつつある．
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The transient receptor potential vanilloid subtype 1 (TRPV1), belonging to the TRPV channel family, is a non-selective, calcium-dependent, cation channel implicated in several pathophysiological processes. Collagen, an extracellular matrix component, can accumulate under pathological conditions and may lead to the destruction of tissue structure, organ dysfunction, and organ failure. Increasing evidence indicates that TRPV1 plays a role in the development and occurrence of fibrotic diseases, including myocardial, renal, pancreatic, and corneal fibrosis. However, the mechanism by which TRPV1 regulates fibrosis remains unclear. This review highlights the comprehensive role played by TRPV1 in regulating pro-fibrotic processes, the potential of TRPV1 as a therapeutic target in fibrotic diseases, as well as the different signaling pathways associated with TRPV1 and fibrosis.
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