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Bernd Nilius - One of the best experts on this subject based on the ideXlab platform.
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The transient Receptor Potential channel TRPA1: from gene to pathophysiology
Pflügers Archiv - European Journal of Physiology, 2012Co-Authors: Bernd Nilius, Giovanni Appendino, Grzegorz OwsianikAbstract:The Transient Receptor Potential Ankyrin 1 channel (TRPA1), is a member of the large TRP family of ion channels, and functions as a Ca2+ permeable non-selective cation channel in many different cell processes, ranging from sensory to homeostatic tasks. TRPA1 is highly conserved across the animal kingdom. The only mammalian TRPA subfamily member, TRPA1, is widely expressed in neuronal (e.g. sensory dorsal root and trigeminal ganglia neurons)- and in non-neuronal cells (e.g. epithelial cells, hair cells). It exhibits 14–19 amino-(N-)terminal ankyrin repeats, an unusual structural feature. The TRPA1 channel is activated by noxious cold (
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Transient Receptor Potential channelopathies
Pflügers Archiv - European Journal of Physiology, 2010Co-Authors: Bernd Nilius, Grzegorz OwsianikAbstract:In the past years, several hereditary diseases caused by defects in transient Receptor Potential channels (TRP) genes have been described. This review summarizes our current knowledge about TRP channelopathies and their possible pathomechanisms. Based on available genetic indications, we will also describe several putative pathological conditions in which (mal)function of TRP channels could be anticipated.
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On the putative role of transient Receptor Potential cation channels in asthma
Clinical & Experimental Allergy, 2009Co-Authors: Barbara Colsoul, Bernd Nilius, Rudi VennekensAbstract:Summary The mammalian transient Receptor Potential (TRP) superfamily consists of 28 mammalian TRP cation channels, which can be subdivided into six main subfamilies: the TRPC (‘Canonical’), TRPV (‘Vanilloid’), TRPM (‘Melastatin’), TRPP (‘Polycystin’), TRPML (‘Mucolipin’) and the TRPA (‘Ankyrin’) groups. Increasing evidence has accumulated during the previous few years that links TRP channels to the cause of several diseases or to critically influence and/or determine their progress. This review focuses on the possible role of TRP channels in the aetiology of asthmatic lung disease.
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Pharmacology of Vanilloid Transient Receptor Potential Cation Channels
Molecular Pharmacology, 2009Co-Authors: Joris Vriens, Giovanni Appendino, Bernd NiliusAbstract:Depending on their primary structure, the 28 mammalian transient Receptor Potential (TRP) cation channels identified so far can be sorted into 6 subfamilies: TRPC (“Canonical”), TRPV (“Vanilloid”), TRPM (“Melastatin”), TRPP (“Polycystin”), TRPML (“Mucolipin”), and TRPA (“Ankyrin”). The TRPV subfamily (vanilloid Receptors) comprises channels critically involved in nociception and thermosensing (TRPV1, TRPV2, TRPV3, and TRPV4), whereas TRPV5 and TRPV6 are involved in renal Ca 2 absorption/reabsorption. Apart from TRPV1, the pharmacology of these channels is still insufficiently known. Furthermore, only few small-molecule ligands for non-TRPV1 vanilloid Receptors have been identified, and little is known of their endogenous ligands, resulting in a substantial “orphan” state for these channels. In this review, we summarize the pharmacological properties of members of the TRPV subfamily, highlighting the critical issues and challenges facing their “deorphanization” and clinical exploitation.
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transient Receptor Potential channels meet phosphoinositides
The EMBO Journal, 2008Co-Authors: Bernd Nilius, Grzegorz Owsianik, Thomas VoetsAbstract:Transient Receptor Potential (TRP) cation channels are unique cellular sensors that are involved in multiple cellular functions, ranging from transduction of sensory signals to the regulation of Ca2+ and Mg2+ homoeostasis. Malfunctioning of TRP channels is now recognized as the cause of several hereditary and acquired human diseases. At the time of cloning of the first Drosophila TRP channel, a close connection between gating and phosphatidylinositol phosphates (PIPs) was already recognized. In this review, we summarize current knowledge about the mechanisms of interaction between TRP channels and PIPs, and discuss the possible functional implications of TRP–PIP interactions to human physiology and pathophysiology.
Arpad Szallasi - One of the best experts on this subject based on the ideXlab platform.
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transient Receptor Potential ankyrin 1 trpa1 antagonists
Pharmaceutical patent analyst, 2015Co-Authors: Delia Preti, Giulia Saponaro, Arpad SzallasiAbstract:The transient Receptor Potential ankyrin 1 (TRPA1) channel is an irritant sensor highly expressed on nociceptive neurons. The clinical use of TRPA1 antagonists is based on the concept that TRPA1 is active during disease states like neuropathic pain. Indeed, in Phase 2a proof-of-concept studies the TRPA1 antagonist GRC17536 has shown efficacy in patients with painful diabetic neuropathy. Moreover, animal studies suggest that the therapeutic value of TRPA1 antagonists extends beyond pain to pruritus, asthma and cough with limited safety concerns. This review provides a comprehensive overview of the patent literature (since 2007) on small-molecule inhibitors of the TRPA1 channel. Despite the clear progress, many unanswered questions remain. Future advancement to Phase 3 studies will assess the real translational Potential of this research field.
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transient Receptor Potential channels as therapeutic targets
Nature Reviews Drug Discovery, 2011Co-Authors: Magdalene M Moran, Michael Allen Mcalexander, Tamas Biro, Arpad SzallasiAbstract:Transient Receptor Potential (TRP) cation channels have been among the most aggressively pursued drug targets over the past few years. Although the initial focus of research was on TRP channels that are expressed by nociceptors, there has been an upsurge in the amount of research that implicates TRP channels in other areas of physiology and pathophysiology, including the skin, bladder and pulmonary systems. In addition, mutations in genes encoding TRP channels are the cause of several inherited diseases that affect a variety of systems including the renal, skeletal and nervous system. This Review focuses on recent developments in the TRP channel-related field, and highlights Potential opportunities for therapeutic intervention.
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Transient Receptor Potential channels as therapeutic targets
Nature Reviews Drug Discovery, 2011Co-Authors: Magdalene M Moran, Michael Allen Mcalexander, Tamas Biro, Arpad SzallasiAbstract:Transient Receptor Potential (TRP) cation channels have been among the most aggressively pursued drug targets over the past few years. Although the initial focus of research was on TRP channels that are expressed by nociceptors, there has been an upsurge in the amount of research that implicates TRP channels in other areas of physiology and pathophysiology, including the skin, bladder and pulmonary systems. In addition, mutations in genes encoding TRP channels are the cause of several inherited diseases that affect a variety of systems including the renal, skeletal and nervous system. This Review focuses on recent developments in the TRP channel-related field, and highlights Potential opportunities for therapeutic intervention. Transient Receptor Potential (TRP) channels are a diverse family of cation channels. Here, the authors discuss recent developments in this area, highlight recent developments and setbacks in the field of pain research and analyse TRP channels as targets for skin, pulmonary and urological disorders. The role of transient Receptor Potential (TRP) channels is best understood in the pain area. As TRP channels are expressed on peripheral nociceptors, where pain is generated, it is hoped that TRP channel blockers will be devoid of the side effects that limit the use of analgesic agents that act on the central nervous system. Several TRP cation channel subfamily V, member 1 (TRPV1) antagonists have advanced to clinical trials, but their side effects (which include hyperthermia and impaired noxious heat detection) have prevented any compounds from progressing beyond Phase II clinical trials. TRPV3 antagonists have shown efficacy in models of neuropathic and inflammatory pain, and one antagonist has entered Phase I clinical trials. An autosomal dominant mutation in the gene that encodes TRP cation channel subfamily A, member 1 (TRPA1) causes familial episodic pain syndrome. Indeed, TRPA1 antagonists have been shown to reduce cold hypersensitivity in rodent models of neuropathic pain without altering normal cold sensation in naive animals. Several TRP channels (such as TRPV1, TRPV4 and TRP cation channel subfamily M, member 8 (TRPM8)) are expressed in the urinary bladder, where they presumably function as sensors of stretch and chemical irritation. TRPV1 and TRPV4 antagonists improve bladder function in rodent models of cystitis. Populations of non-neuronal cells within the skin express many different types of TRP channels that are implicated in the regulation of several key cutaneous functions including skin-derived pruritus, proliferation, differentiation and inflammatory processes. TRPA1 and TRPV1 serve as polymodal sensors in the mammalian respiratory tract that integrate varied inflammatory, oxidant and hazardous irritant stimuli to produce noxious sensations (for example, breathlessness, the urge to cough and nasopharyngeal pain) and respiratory reflexes such as coughing. Several TRP channels — including members of TRP cation channel subfamily C (TRPC) and TRPV — influence the process of gas exchange by regulating airflow, blood flow and airway permeability. Mutations in at least six of the 28 members of the TRP channel superfamily are associated with heritable genetic diseases in humans. These mutations have implicated TRP channels in many pathophysiological states and expanded our understanding of the physiological role of these channels. The role of TRP channels in the brain remains to be elucidated, but it seems to be clear that some members of the superfamily are involved in neuronal excitability and neurotransmitter release. Genetic deletion of TRPC5 leads to an anxiolytic phenotype, whereas a point mutation in TRPC3 leads to ataxia. TRP channels also serve important functions in other diseases that are not fully explored in this Review. For example, cancer and metabolic diseases will be particularly interesting to watch in the future.
Donna H Wang - One of the best experts on this subject based on the ideXlab platform.
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Transient Receptor Potential vanilloid in blood pressure regulation.
Current opinion in nephrology and hypertension, 2013Co-Authors: Michael Hollis, Donna H WangAbstract:PURPOSE OF REVIEW The involvement of neurohormonal factors in the pathogenesis of hypertension has been extensively studied. However, the mechanisms underlying the role of the transient Receptor Potential vanilloid type 1 (TRPV1) channels in hypertension are still largely unknown. This review presents some of the most recent findings regarding the Potential mechanisms of TRPV1 in mediating blood pressure, the pathophysiology of hypertension, and its related disorders. RECENT FINDINGS TRPV1 may be activated by exogenous vanilloid or endo-vanilloid compounds and its function modulated by vasoactive mediators. TRPV1 also interacts with various physiological and pathophysiological systems involved in salt and water homeostasis and cardiovascular homeostasis. Impairment of TRPV1 signaling may contribute to the pathogenesis of diseases such as hypertension, heart failure, atherosclerosis, diabetes, obesity, myocardial ischemia, and stroke. SUMMARY Accumulating evidence implicates TRPV1 as serving a key role in cardiovascular health by regulating cardiovascular function and protecting against cardiovascular injury. Given the large prevalence of hypertension and its related disorders, the possible involvement of TRPV1 makes it a Potential target of therapy for cardiovascular disease. Future study of TRPV1 may enhance our understanding of several cardiovascular diseases and may unveil novel pharmacological strategies for treating hypertension.
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hypotension induced by activation of the transient Receptor Potential vanilloid 4 channels role of ca2 activated k channels and sensory nerves
Journal of Hypertension, 2010Co-Authors: Feng Gao, Donna H WangAbstract:Objective To examine the mechanisms involved in hypotension induced by transient Receptor Potential vanilloid 4 (TRPV4) activation.
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transient Receptor Potential vanilloid channels in hypertension inflammation and end organ damage an imminent target of therapy for cardiovascular disease
Current Opinion in Cardiology, 2008Co-Authors: Donna H WangAbstract:Purpose of review The possible role of several neurohormonal factors in pathogenesis of hypertension has been studied extensively both in humans and in experimental animal models. However, controversial data from some previous studies are indecisive and call for reassessment and development of new targets. This mini-review presents some of the most recent findings about the role of transient Receptor Potential vanilloid type 1 channels in the development of hypertension and its pathology. Recent findings The transient Receptor Potential vanilloid type 1, channel activated by novel endovanilloids or altered pH, temperature, and/or local hemodynamics, may serve as a distinct molecular sensor detecting sodium and water balance and may play a role in preventing salt-induced hypertension and tissue damage. Impairment of the function of the transient Receptor Potential vanilloid type 1 channels may contribute to increased salt sensitivity, inflammation, and end organ damage. Summary Emerging evidence indicates that the transient Receptor Potential vanilloid type 1 channel plays a key role in cardiovascular health and disease by acting as a sensor and regulator of cardiovascular homeostasis and a protector against cardiovascular injury. Given the huge population who suffers from cardiovascular disease, the study of the transient Receptor Potential vanilloid channels may improve our understanding of pathogenesis of several common cardiovascular disorders and may lead to the development of therapy for hypertension, inflammation, and organ damage.
Tibor Rohacs - One of the best experts on this subject based on the ideXlab platform.
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Sphingosine and the transient Receptor Potential channel kinase(s)
British journal of pharmacology, 2013Co-Authors: Tibor RohacsAbstract:Transient Receptor Potential melastatin 7 (TRPM7) is a multifunctional ion channel playing crucial roles during development. TRPM7 is a member of the highly diverse TRP ion channel family. Most TRP channels are regulated by membrane phospholipids, especially phosphoinositides. In this issue of the British Journal of Pharmacology, Qin et al. describes the regulation of TRPM7 and its close homologue TRPM6 by a different kind of membrane lipid: sphingosine. The study finds that sphingosine is a potent and specific inhibitor of TRPM7 and TRPM6 channels. This commentary briefly summarizes the findings of the study, their Potential significance and discusses open question and future directions. Linked Article This article is a commentary on Xin Qin et al., pp. 1294–1312 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12012
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Phosphoinositide regulation of non-canonical transient Receptor Potential channels.
Cell calcium, 2009Co-Authors: Tibor RohacsAbstract:Transient Receptor Potential (TRP) channels are involved in a wide range of physiological processes, and characterized by diverse activation mechanisms. Phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate [PIP(2), or PtdIns(4,5)P(2)] recently emerged as regulators of many TRP channels. Several TRP channels require PIP(2) for activity, and depletion of the lipid inhibits them. For some TRP channels, however, phosphoinositide regulation seems more complex, both activating and inhibitory effects have been reported. This review will discuss phosphoinositide regulation of members of the TRPM (Melastatin), TRPV (Vanilloid), TRPA (Ankyrin) and TRPP (Polycystin) families. Lipid regulation of TRPC (Canonical) channels is discussed elsewhere in this volume.
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regulation of transient Receptor Potential trp channels by phosphoinositides
Pflügers Archiv: European Journal of Physiology, 2007Co-Authors: Tibor Rohacs, Bernd NiliusAbstract:This review summarizes the modulation of transient Receptor Potential (TRP) channels, by phosphoinositides. TRP channels are characterized by polymodal activation and a surprising complexity of regulation mechanisms. Possibly, most if not all TRP channels are modulated by phosphoinositides. Modulation by phosphatidylinositol 4,5-biphosphate (PIP2) has been shown in detail for TRP vanilloid (TRPV) 1, TRPV5, TRP melastatin (TRPM) 4, TRPM5, TRPM7, TRPM8, TRP polycystin 2, and the Drosophila TPR-like (TRPL) channels. This review describes mechanisms of modulation of TRP channels mainly by PIP2 and discusses some future challenges of this fascinating topic.
Grzegorz Owsianik - One of the best experts on this subject based on the ideXlab platform.
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The transient Receptor Potential channel TRPA1: from gene to pathophysiology
Pflügers Archiv - European Journal of Physiology, 2012Co-Authors: Bernd Nilius, Giovanni Appendino, Grzegorz OwsianikAbstract:The Transient Receptor Potential Ankyrin 1 channel (TRPA1), is a member of the large TRP family of ion channels, and functions as a Ca2+ permeable non-selective cation channel in many different cell processes, ranging from sensory to homeostatic tasks. TRPA1 is highly conserved across the animal kingdom. The only mammalian TRPA subfamily member, TRPA1, is widely expressed in neuronal (e.g. sensory dorsal root and trigeminal ganglia neurons)- and in non-neuronal cells (e.g. epithelial cells, hair cells). It exhibits 14–19 amino-(N-)terminal ankyrin repeats, an unusual structural feature. The TRPA1 channel is activated by noxious cold (
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Transient Receptor Potential channelopathies
Pflügers Archiv - European Journal of Physiology, 2010Co-Authors: Bernd Nilius, Grzegorz OwsianikAbstract:In the past years, several hereditary diseases caused by defects in transient Receptor Potential channels (TRP) genes have been described. This review summarizes our current knowledge about TRP channelopathies and their possible pathomechanisms. Based on available genetic indications, we will also describe several putative pathological conditions in which (mal)function of TRP channels could be anticipated.
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transient Receptor Potential channels meet phosphoinositides
The EMBO Journal, 2008Co-Authors: Bernd Nilius, Grzegorz Owsianik, Thomas VoetsAbstract:Transient Receptor Potential (TRP) cation channels are unique cellular sensors that are involved in multiple cellular functions, ranging from transduction of sensory signals to the regulation of Ca2+ and Mg2+ homoeostasis. Malfunctioning of TRP channels is now recognized as the cause of several hereditary and acquired human diseases. At the time of cloning of the first Drosophila TRP channel, a close connection between gating and phosphatidylinositol phosphates (PIPs) was already recognized. In this review, we summarize current knowledge about the mechanisms of interaction between TRP channels and PIPs, and discuss the possible functional implications of TRP–PIP interactions to human physiology and pathophysiology.
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Vanilloid Transient Receptor Potential Cation Channels : An Overview
Current Pharmaceutical Design, 2008Co-Authors: Rudi Vennekens, Grzegorz Owsianik, Bernd NiliusAbstract:The mammalian branch of the Transient Receptor Potential (TRP) superfamily of cation channels consists of 28 members. They can be subdivided in six main subfamilies: the TRPC (‘Canonical’), TRPV (‘Vanilloid’), TRPM (‘Melastatin’), TRPP (‘Polycystin’), TRPML (‘Mucolipin’) and the TRPA (‘Ankyrin’) group. The TRPV subfamily comprises channels that are critically involved in nociception and thermo-sensing (TRPV1, TRPV2, TRPV3, TRPV4) as well as highly Ca2+ selective channels involved in Ca2+ absorption/ reabsorption in mammals (TRPV5, TRPV6). In this review we summarize fundamental physiological properties of all TRPV members in the light of various cellular functions of these channels and their significance in the systemic context of the mammalian organism.
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transient Receptor Potential cation channels in disease
Physiological Reviews, 2007Co-Authors: Bernd Nilius, Grzegorz Owsianik, Thomas Voets, John A PetersAbstract:The transient Receptor Potential (TRP) superfamily consists of a large number of cation channels that are mostly permeable to both monovalent and divalent cations. The 28 mammalian TRP channels can be subdivided into six main subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin) groups. TRP channels are expressed in almost every tissue and cell type and play an important role in the regulation of various cell functions. Currently, significant scientific effort is being devoted to understanding the physiology of TRP channels and their relationship to human diseases. At this point, only a few channelopathies in which defects in TRP genes are the direct cause of cellular dysfunction have been identified. In addition, mapping of TRP genes to susceptible chromosome regions (e.g., translocations, breakpoint intervals, increased frequency of polymorphisms) has been considered suggestive of the involvement of these channels in hereditary diseases. Moreover, strong indications of the involvement of TRP channels in several diseases come from correlations between levels of channel expression and disease symptoms. Finally, TRP channels are involved in some systemic diseases due to their role as targets for irritants, inflammation products, and xenobiotic toxins. The analysis of transgenic models allows further extrapolations of TRP channel deficiency to human physiology and disease. In this review, we provide an overview of the impact of TRP channels on the pathogenesis of several diseases and identify several TRPs for which a causal pathogenic role might be anticipated.
