Regulation of leptin receptor-expressing neurons in the brainstem by TRPV1
Andrea ZsombokYanyan JiangHong GaoImran J. AnwarKavon Rezai‐ZadehCourtney L. EnixHeike MünzbergAndrei V. Derbenev
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Abstract:
The central nervous system plays a critical role in the regulation of feeding behavior and whole-body metabolism via controlling the autonomic output to the visceral organs. Activity of the parasympathetic neurons in the dorsal motor nucleus of the vagus (DMV) determines the vagal tone and thereby modulates the function of the subdiaphragmatic organs. Leptin is highly involved in the regulation of food intake and alters neuronal excitability of brainstem neurons. Transient receptor potential vanilloid type 1 (TRPV1) has also been shown to increase neurotransmission in the brainstem and we tested the hypothesis that TRPV1 regulates presynaptic neurotransmitter release to leptin receptor-expressing (LepRbEGFP) DMV neurons. Whole-cell patch-clamp recordings were performed to determine the effect of TRPV1 activation on excitatory and inhibitory postsynaptic currents (EPSC, IPSC) of LepRbEGFP neurons in the DMV. Capsaicin, a TRPV1 agonist increased the frequency of miniature EPSCs in 50% of LepRbEGFP neurons without altering the frequency of miniature IPSCs in the DMV. Stomach-projecting LepRbEGFP neurons were identified in the DMV using the transsynaptic retrograde viral tracer PRV-614. Activation of TRPV1 increased the frequency of mEPSC in ~50% of stomach-related LepRbEGFP DMV neurons. These data demonstrate that TRPV1 increases excitatory neurotransmission to a subpopulation of LepRbEGFP DMV neurons via presynaptic mechanisms and suggest a potential interaction between TRPV1 and leptin signaling in the DMV.Keywords:
Dorsal motor nucleus
Premovement neuronal activity
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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This chapter contains sections titled: Overview Introduction Temperature-sensitive TRP (thermoTRP) channels are multifaceted sensors TRPV1, the archetypal thermoTRP channel, is activated by capsaicin and endovanilloids TRPV1 antagonists: a preclinical overview TRPV2, a structural homolog of TRPV1 TRPV3, a warm-sensitive relative of TRPV1 TRPV4, a polymodal channel with a widespread diversity of activation mechanisms TRPA1, the cold receptor highly coexpressed with the hot TRPV1 TRPM8, the cool menthol receptor Conclusions References
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Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel,which can be activated by multiple pathways during the course of the diseases.Recent studies indicate that primary sensory neurons of the pancreas express TRPV1 receptor and the activation of TRPV1 receptor promotes pancreatic inflammation.Moreover,blockade of these transient receptor potential channels can greatly ameliorate the pain response in experimental pancreatitis.
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A subset of transient receptor potential (TRP) channels exhibits activity that is highly sensitive to temperature changes and is expressed in sensory tissues, such as nociceptors and skin. Some of these thermosensitive TRP channels, such as TRPV1, TRPV4 and TRPA1, are activated or sensitized by molecules generated by inflammation and/or cell damage. TRPV1, also known as the capsaicin receptor, is particularly important in mediating hyperalgesic responses in inflammatory pain states, as demonstrated by research in knockout animals and with small-molecule antagonists. It is anticipated that TRPV1 antagonists, and perhaps antagonists at other thermosensitive TRP channels, will provide new therapeutic options with which to treat clinical pain.
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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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The treatment of chronic pain with new therapies that lack the side effects of existing analgesics is one of medicine9s great unmet needs. Toward this goal, antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel have shown some promise. However, the development of these compounds has been hindered by an unpleasant on-target hyperthermic side effect. With compelling evidence, the accompanying critical review by Romanovsky et al. (p. 228) regarding TRPV1 takes a position on the sites of action of TRPV1 agonists and antagonists on the thermoregulatory system that controls this side effect. From this comes insight on potential ways to overcome the unwanted hyperthermic action of TRPV1 antagonists.
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There is emerging evidence that transient receptor potential (TRP) ion channels expressed in sensory neurons are important for the transduction of chemical, thermal and mechanical signals. Increasing research efforts are directed at understanding the roles of sensory TRP channels in acute and chronic pain. Studies using RNAi techniques to reduce the levels of individual TRP channels or genetically modified mice lacking specific channels are being complemented with pharmacological studies using newly discovered investigational compounds. These studies are providing evidence that drugs that interfere with the function of TRPA1, TRPM8, TRPV4 or TRPV3 may be useful in treating pain.
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Transient receptor potential (TRP) ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) receptors are implicated in modulation of cough and nociception. In vivo, TRPA1 and TRPV1 are often co-expressed in neurons and TRPA1V1 hetero-tetramer formation is noted in cells co-transfected with the respective expression plasmids. In order to understand the impact of TRP receptor interaction on activity, we created stable cell lines expressing the TRPA1, TRPV1 and co-expressing the TRPA1 and TRPV1 (TRPA1V1) receptors. Among the 600 compounds screened against these receptors, we observed a number of compounds that activated the TRPA1, TRPV1 and TRPA1V1 receptors; compounds that activated TRPA1 and TRPA1V1; compounds that activated TRPV1 and TRPA1V1; compounds in which TRPA1V1 response was modulated by either TRPA1 or TRPV1; and compounds that activated only TRPV1 or TRPA1 or TRPA1V1; and one compound that activated TRPA1 and TRPV1, but not TRPA1V1. These results suggest that co-expression of TRPA1 and TRPV1 receptors imparts unique activation profiles different from that of cells expressing only TRPA1 or TRPV1.
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