Showing papers on "TRPV published in 2007"
TL;DR: An overview of the impact of TRP channels on the pathogenesis of several diseases is provided and several TRPs for which a causal pathogenic role might be anticipated are identified.
Abstract: 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.
1,325 citations
TL;DR: It is reported that TRPV1 antagonists representing various chemotypes cause an increase in body temperature (hyperthermia), identifying a potential issue for their clinical development and indicating that tonic TRPv1 activation regulates body temperature.
Abstract: The vanilloid receptor TRPV1 (transient receptor potential vanilloid 1) is a cation channel that serves as a polymodal detector of pain-producing stimuli such as capsaicin, protons (pH <5.7), and heat. TRPV1 antagonists block pain behaviors in rodent models of inflammatory, neuropathic, and cancer pain, suggesting their utility as analgesics. Here, we report that TRPV1 antagonists representing various chemotypes cause an increase in body temperature (hyperthermia), identifying a potential issue for their clinical development. Peripheral restriction of antagonists did not eliminate hyperthermia, suggesting that the site of action is predominantly outside of the blood–brain barrier. Antagonists that are ineffective against proton activation also caused hyperthermia, indicating that blocking capsaicin and heat activation of TRPV1 is sufficient to produce hyperthermia. All TRPV1 antagonists evaluated here caused hyperthermia, suggesting that TRPV1 is tonically activated in vivo and that TRPV1 antagonism and hyperthermia are not separable. TRPV1 antagonists caused hyperthermia in multiple species (rats, dogs, and monkeys), demonstrating that TRPV1 function in thermoregulation is conserved from rodents to primates. Together, these results indicate that tonic TRPV1 activation regulates body temperature.
296 citations
TL;DR: It is concluded that tonic activation of TRPV1 channels in the abdominal viscera by yet unidentified nonthermal factors inhibits skin vasoconstriction and thermogenesis, thus having a suppressive effect on Tb.
Abstract: An involvement of the transient receptor potential vanilloid (TRPV) 1 channel in the regulation of body temperature (T(b)) has not been established decisively. To provide decisive evidence for such an involvement and determine its mechanisms were the aims of the present study. We synthesized a new TRPV1 antagonist, AMG0347 [(E)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylamide], and characterized it in vitro. We then found that this drug is the most potent TRPV1 antagonist known to increase T(b) of rats and mice and showed (by using knock-out mice) that the entire hyperthermic effect of AMG0347 is TRPV1 dependent. AMG0347-induced hyperthermia was brought about by one or both of the two major autonomic cold-defense effector mechanisms (tail-skin vasoconstriction and/or thermogenesis), but it did not involve warmth-seeking behavior. The magnitude of the hyperthermic response depended on neither T(b) nor tail-skin temperature at the time of AMG0347 administration, thus indicating that AMG0347-induced hyperthermia results from blockade of tonic TRPV1 activation by nonthermal factors. AMG0347 was no more effective in causing hyperthermia when administered into the brain (intracerebroventricularly) or spinal cord (intrathecally) than when given systemically (intravenously), which indicates a peripheral site of action. We then established that localized intra-abdominal desensitization of TRPV1 channels with intraperitoneal resiniferatoxin blocks the T(b) response to systemic AMG0347; the extent of desensitization was determined by using a comprehensive battery of functional tests. We conclude that tonic activation of TRPV1 channels in the abdominal viscera by yet unidentified nonthermal factors inhibits skin vasoconstriction and thermogenesis, thus having a suppressive effect on T(b).
202 citations
TL;DR: Genetic evidence supports an excitatory role of diacylglycerol (DAG) for the dTRP's, although curiously only DAG metabolites (PUFAs) have been found to activate the Drosophila channels.
Abstract: The transient receptor potential (TRP) ion channel family was the last major ion channel family to be discovered. The prototypical member (dTRP) was identified by a forward genetic approach in Drosophila, where it represents the transduction channel in the photoreceptors, activated downstream of a Gq-coupled PLC. In the meantime 29 vertebrate TRP isoforms are recognized, distributed amongst seven subfamilies (TRPC, TRPV, TRPM, TRPML, TRPP, TRPA, TRPN). They subserve a wide range of functions throughout the body, most notably, though by no means exclusively, in sensory transduction and in vascular smooth muscle. However, their precise physiological roles and mechanism of activation and regulation are still only gradually being revealed. Most TRP channels are subject to multiple modes of regulation, but a common theme amongst the TRPC/V/M subfamilies is their regulation by lipid messengers. Genetic evidence supports an excitatory role of diacylglycerol (DAG) for the dTRP's, although curiously only DAG metabolites (PUFAs) have been found to activate the Drosophila channels. TRPC2,3,6 and 7 are widely accepted as DAG-activated channels, although TRPC3 can also be regulated via a store-operated mechanism. More recently PIP2 has been shown to be required for activity of TRPV5, TRPM4,5,7 and 8, whilst it may inhibit TRPV1 and the dTRPs. Although compelling evidence for a direct interaction of DAG with the TRPC channels is lacking, mutagenesis studies have identified putative PIP2-interacting domains in the C-termini of several TRPV and TRPM channels.
179 citations
TL;DR: Cultivated cortical astrocytes express the transient receptor potential vanilloid-related channel 4 (TRPV 4), a Ca(2+)-permeable cation channel gated by a variety of stimuli, including cell swelling, which supports the view that TRPV4 might participate in astroglial osmosensation and thus play a key role in brain volume homeostasis.
173 citations
TL;DR: Results indicate that a substantial fraction of TRP channels in the plasma membrane of cotransfected cells were heteromeric, and Interestingly, heteromersic TRPV channels exhibit intermediate conductance levels and gating kinetic properties.
Abstract: Heat-sensitive transient receptor potential (TRP) channels (TRPV1–4) form the major cellular sensors for detecting temperature increases. Homomeric channels formed by thermosensitive TRPV subunits exhibit distinct temperature thresholds. While these subunits do share significant sequence similarity, whether they can coassemble into heteromeric channels has been controversial. In the present study we investigated the coassembly of TRPV subunits using both spectroscopy-based fluorescence resonance energy transfer (FRET) and single-channel recordings. Fluorescent protein–tagged TRPV subunits were coexpressed in HEK 293 cells; FRET between different subunits was measured as an indication of the formation of heteromeric channels. We observed strong FRET when fluorescence signals were collected selectively from the plasma membrane using a “spectra FRET” approach but much weaker or no FRET from intracellular fluorescence. In addition, no FRET was detected when TRPV subunits were coexpressed with members of the TRPM subfamily or CLC-0 chloride channel subunits. These results indicate that a substantial fraction of TRP channels in the plasma membrane of cotransfected cells were heteromeric. Single-channel recordings confirmed the existence of multiple heteromeric channel forms. Interestingly, heteromeric TRPV channels exhibit intermediate conductance levels and gating kinetic properties. As these subunits coexpress both in sensory neurons and in other tissues, including heart and brain, coassembly between TRPV subunits may contribute to greater functional diversity.
167 citations
TL;DR: It is concluded that activation of urothelial TRPV4 by 4α-PDD and release of mediators such as ATP trigger a novel neural mechanism that regulates the late phase of detrusor muscle contraction after micturition.
Abstract: The ion channel transient receptor potential vanilloid (TRPV) 4 can be activated by hypo-osmolarity, heat, or certain lipid compounds. Here, we demonstrate expression of functional TRPV4 protein in the urothelium lining the renal pelvis, ureters, urinary bladder, and urethra. Exposure of cultured rat urothelial cells from the urinary bladder to the TRPV4-selective agonist 4α-phorbol 12,13-didecanoate (4α-PDD) promoted Ca 2+ influx, evoked ATP release, and augmented the ATP release evoked by hypo-osmolarity. In awake rats during continuous infusion cystometrograms, intravesical administration of 4α-PDD (10–100 μM) increased maximal micturition pressure by 51%, specifically by augmenting the portion of each intravesical pressure wave that follows high-frequency urethral oscillations and voiding. This unusual pharmacological effect was prevented by intravesical pretreatment with the nonselective ATP receptor antagonist, pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (100 μM), systemic treatment with the selective P2X 3 purinergic antagonist 5-([(3-phenoxybenzyl)[1 S )-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl)-1,2,4-benzenetricarboxylic acid (A317491) (250 μmol/kg), or urethane anesthesia, but was unaffected by capsaicin pretreatment (100 mg/kg s.c.) or denervation of the urethral sphincter. 4α-PDD (1–100 μM) did not alter the contractility to electrical stimulation of excised bladder strips. We conclude that activation of urothelial TRPV4 by 4α-PDD and release of mediators such as ATP trigger a novel neural mechanism that regulates the late phase of detrusor muscle contraction after micturition. These data raise the possibility that TRPV4 channels in the urothelium could contribute to abnormal bladder activity.
144 citations
TL;DR: A clear role for TRPV1 is demonstrated in the excitability of particularly low threshold bladder afferents, suggesting that TRpV1 may play an important role in normal bladder function.
Abstract: Understanding bladder afferent pathways may reveal novel targets for therapy of lower urinary tract disorders such as overactive bladder syndrome and cystitis Several potential candidate molecules have been postulated as playing a significant role in bladder function One such candidate is the transient receptor potential vanilloid 1 (TRPV1) ion channel Mice lacking the TRPV1 channel have altered micturition thresholds suggesting that TRPV1 channels may play a role in the detection of bladder filling The aim of this study was therefore to investigate the role of TRPV1 receptors in controlling bladder afferent sensitivity in the mouse using pharmacological receptor blockade and genetic deletion of the channel Multiunit afferent activity was recorded in vitro from bladder afferents taken from wild-type (TRPV+/+) mice and knockout (TRPV1−/−) mice In wild-type preparations, ramp distension of the bladder to a maximal pressure of 40 mmHg produced a graded increase in afferent activity Bath application of the TRPV1 antagonist capsazepine (10 μm) caused a significant attenuation of afferent discharge in TRPV1+/+ mice Afferent responses to distension were significantly attenuated in TRPV1−/− mice in which sensitivity to intravesical hydrochloric acid (50 mm) and capsaicin (10 μm) were also blunted Altered mechanosensitivity occurred in the absence of any changes in the pressure–volume relationship during filling indicating that this was not secondary to a change in bladder compliance Single-unit analysis was used to classify individual afferents into low-threshold and high-threshold fibres Low threshold afferent responses were attenuated in TRPV1−/− mice compared to the TRPV1+/+ littermates while surprisingly high threshold afferent sensitivity was unchanged While TRPV1 channels are not considered to be mechanically gated, the present study demonstrates a clear role for TRPV1 in the excitability of particularly low threshold bladder afferents This suggests that TRPV1 may play an important role in normal bladder function
143 citations
TL;DR: Indirect evidence suggests that TRPV channels may play a part in the pathogenesis of certain respiratory diseases such as asthma and chronic cough, and the potential use of TRpV antagonists as a novel therapy for these diseases certainly merits further investigation.
128 citations
TL;DR: Most recent data concerning TRP vanilloid (TRPV) type 6, TRP melastatin (TRPM) type 1 and 8 channels and their relevance for common human cancer types will be highlighted in this review.
125 citations
TL;DR: Mechanisms of modulation of TRP channels mainly by PIP2 are described and some future challenges of this fascinating topic are discussed.
Abstract: 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.
TL;DR: This is the first study to demonstrate the presence of bothTRPV1 and TRPV2 in human peripheral lymphocytes, and the role of TRpV channels in these cells is determined.
TL;DR: Emerging evidence of the pathophysiological role of TRP channels has yielded promising candidates for molecular entities mediating Ca(2+) homeostasis disruption in AD and some TRP "suspects" for which a role in AD can be anticipated are highlighted.
TL;DR: An assay based on cell lines stably expressing mouse TRPV2 channels and intracellular calcium measurements is developed to perform a pharmacological profiling of the channel and it is demonstrated that hTRpV2 exerts a dominant-negative effect on 2APB activation of native rodent TRP vdW channels and thus may provide an interesting tool to investigate cellular functions of TRPv2 channels.
Abstract: Despite its expression in different cell types, transient receptor potential V2 (TRPV2) is still the most cryptic members of the TRPV channel family. 2-Aminoethoxydiphenyl borate (2APB) has been shown to be a common activator of TRPV1, TRPV2, and TRPV3, but 2APB-triggered TRPV2 activation remains to be thoroughly characterized. In this study, we have developed an assay based on cell lines stably expressing mouse TRPV2 channels and intracellular calcium measurements to perform a pharmacological profiling of the channel. Phenyl borate derivatives were found to activate mouse TRPV2 with similar potencies and thus were used to screen a panel of channel blockers. Besides the classic TRP inhibitors ruthenium red (RR) and 1-(beta-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SKF96365), two potassium channel blockers, tetraethylammonium (TEA) and 4-aminopyridine, and an inhibitor of capacitative calcium entry, 1-(2-(trifluoromethyl) phenyl) imidazole (TRIM), were found to inhibit TRPV2 activation by 100 microM 2APB. Activation by 300 microM 2APB, however, could only be inhibited by RR and TRIM. Electrophysiological recordings demonstrated that TEA inhibition was use-dependent, suggesting that high concentrations of 2APB might induce a progressive conformational change of the channel. Comparison of TRPV2 orthologs revealed that the human channel was insensitive to 2APB. Analysis of chimeric constructs of mouse and human TRPV2 channels showed that the molecular determinants of 2APB sensitivity could be localized to the intracellular amino and carboxyl domains. Finally, using lentiviral-driven expression, we demonstrate that hTRPV2 exerts a dominant-negative effect on 2APB activation of native rodent TRPV2 channels and thus may provide an interesting tool to investigate cellular functions of TRPV2 channels.
TL;DR: A role of the TRP domain is uncovered in intersubunit interactions near the channel gate that contribute to the coupling of stimulus sensing to channel opening.
Abstract: Transient receptor potential vanilloid receptor subtype 1 (TRPV1) is an ionotropic receptor activated by temperature and chemical stimuli. The C-terminal region that is adjacent to the channel gate, recognized as the TRP domain, is a molecular determinant of receptor assembly. However, the role of this intracellular domain in channel function remains elusive. Here, we show that replacement of the TRP domain of TRPV1 with the cognate region of TRPV channels (TRPV2-TRPV6) did not affect receptor assembly and trafficking to the cell surface, although those receptors containing the TRP domain of the distantly related TRPV5 and TRPV6 did not display ion channel activity. Notably, functional chimeras exhibited an impaired sensitivity to the activating stimuli, consistent with a significant contribution of this protein domain to channel function. At variance with TRPV1, voltage-dependent gating of chimeric channels could not be detected in the absence of capsaicin and/or heat. Biophysical analysis of functional chimeras revealed that the TRP domain appears to act as a molecular determinant of the activation energy of channel gating. Together, these findings uncover a role of the TRP domain in intersubunit interactions near the channel gate that contribute to the coupling of stimulus sensing to channel opening.
TL;DR: This study examined the regulation of all TRPC members (TRPC1–C7) throughout embryonic and postnatal development of the dorsal root ganglion (DRG) and nodose ganglions (NG) of mice and suggested important roles of the TRPC family of channels in sensory physiology of both nociceptive as well as nonnociception classes of neurons.
Abstract: Transient receptor potential (TRP) channels play essential roles in sensory physiology and their expression in different classes of sensory neurons reflect distinct receptive properties of these neurons. While expression of the TRPV, TRPA, and to a certain degree TRPM classes of channels has been studied in sensory neurons, little is known about the expression and regulation of TRPC channels. In this study we examined the regulation of all TRPC members (TRPC1–C7) throughout embryonic and postnatal development of the dorsal root ganglion (DRG) and nodose ganglion (NG). In adult mice, mRNAs for all channels were present in the DRG, with TRPC1, 3, and 6 being the most abundant, TRPC2, C4, and C5 at lower levels, and TRPC7 at very low levels. While TRPC2 mRNAs were downregulated from high levels at embryonic (E) day 12 and E14 until adult, TRPC4, C5, and C7 expressions increased from E12 to peak levels at E18. TRPC1, C3, and C6, the most abundant TRPC channel mRNAs, increased progressively from E12 to adult. Expression and regulation of TRPC channels mRNAs in the NG were unexpectedly similar to the DRG. TRPC1 and C2 was expressed in the neurofilament-200 (NF-200)-positive large size subclass of neurons, while TRPC3 mRNAs expression, which stained up to 35% of DRG neurons, was almost exclusively present in nonpeptidergic isolectin B4 (IB4)-positive small size neurons that were largely TRPV1-negative. Our results suggest important roles of the TRPC family of channels in sensory physiology of both nociceptive as well as nonnociceptive classes of neurons. J. Comp. Neurol. 503:35–46, 2007. © 2007 Wiley-Liss, Inc.
Patent•
23 Apr 2007TL;DR: In this article, arachidonic acid derivatives and analogs are used to activate transient receptor potential vanilloid-1 channels (TRPVl) for the treatment of patients demonstrating symptoms of pathological conditions.
Abstract: The present inventions relate to therapeutic compositions comprising, and methods utilizing, arachidonic acid derivatives and analogs for treatment of patients demonstrating symptoms of pathological conditions. Specifically, the inventions relate to therapeutic compositions for activating transient receptor potential vanilloid-1 channels (TRPVl). Additionally, therapeutic compositions are provided for increasing TRPVl -type responses. These pathological conditions include, but are limited to, hypertension, in particular salt induced hypertension, and cardiovascular complications, including myocardial infarction, kidney dysfunction, diabetes, and inflammation. Further, the inventions relate to drug screening methods for providing additional therapeutic compounds.
01 Jan 2007
TL;DR: An introduction to TRP Channels and TRP Proteins and Specific Cellular Functions is presented.
Abstract: An Introduction on TRP Channels.- An Introduction on TRP Channels.- TRPC Channel Subfamily.- TRPC1 Ca2+-Permeable Channels in Animal Cells.- TRPC2: Molecular Biology and Functional Importance.- TRPC3: A Multifunctional, Pore-Forming Signalling Molecule.- Ionic Channels Formed by TRPC4.- Canonical Transient Receptor Potential 5.- TRPC6.- TRPC7.- TRPV Channel Subfamily.- Capsaicin Receptor: TRPV1 A Promiscuous TRP Channel.- 2-Aminoethoxydiphenyl Borate as a Common Activator of TRPV1, TRPV2, and TRPV3 Channels.- TRPV4.- TRPV5, the Gateway to Ca2+ Homeostasis.- TRPV6.- TRPM Channel Subfamily.- TRPM2.- TRPM3.- Insights into TRPM4 Function, Regulation and Physiological Role.- TRPM5 and Taste Transduction.- TRPM6: A Janus-Like Protein.- The Mg2+ and Mg2+-Nucleotide-Regulated Channel-Kinase TRPM7.- TRPM8.- Other TRP Channels.- TRPA1.- TRPP2 Channel Regulation.- TRP Proteins and Specific Cellular Functions.- Know Thy Neighbor: A Survey of Diseases and Complex Syndromes that Map to Chromosomal Regions Encoding TRP Channels.- TRP Channels of the Pancreatic Beta Cell.- TRP Channels in Platelet Function.- TRP Channels in Lymphocytes.- Link Between TRPV Channels and Mast Cell Function.- TRPV Channels' Role in Osmotransduction and Mechanotransduction.- Nociception and TRP Channels.- TRP Proteins - Integrators of Multiple Inputs.- Regulation of TRP Ion Channels by Phosphatidylinositol-4,5-Bisphosphate.- TRPC, cGMP-Dependent Protein Kinases and Cytosolic Ca2+.- Trafficking of TRP Channels: Determinants of Channel Function.- TRPC Channels: Interacting Proteins.- TRPC Channels: Integrators of Multiple Cellular Signals.- Phospholipase C-Coupled Receptors and Activation of TRPC Channels.- Erratum.- Erratum.
TL;DR: To localize aquaporin (AQP)2, vasopressin type 2 receptor (V2‐R), and transient receptor potential channel vanilloid subfamily 1, 4 (TRPV1, TRPV4) in the human endolymphatic sac (ES).
Abstract: Objective: To localize aquaporin (AQP)2, vasopressin type 2 receptor (V2-R), and transient receptor potential channel vanilloid subfamily 1, 4 (TRPV1, TRPV4) in the human endolymphatic sac (ES).
Methods: Three samples of human ES were sampled during the removal of vestibular schwannoma by way of the translabyrinthine approach. The samples were immediately fixed in 4% paraformaldehyde and embedded in OCT compound; immunohistochemistry was performed with AQP2, V2-R, TRPV1, and TRPV4 polyclonal antibodies.
Results: AQP2, V2-R, TRPV1, and TRPV4 proteins were detected in the epithelial layer of the ES but were not observed in connective tissue around the ES. TRPV1 was also expressed in blood vascular endothelial cells of the connective tissue of ES.
Conclusions: AQP2, V2-R, and TRPV4 were expressed in the luminal epithelium of human ES. The same characteristic distribution of water and ion channels is seen in the kidney, where a significant amount of fluid is filtrated and resorbed. ES probably plays an active role in the homeostasis of the endolymph.
TL;DR: The results identify a specific set of heteromeric TRPV channels that redundantly regulate neuroendocrine function and show that a subunit combination that functions in sensory neurons is also present in neuro endocrine cells but has no detectable function in these cells.
Abstract: Transient receptor potential (TRP) channel subunits form homotetramers that function in sensory transduction. Heteromeric channels also form, but their physiological subunit compositions and functions are largely unknown. We found a dominant-negative mutant of the C. elegans TRPV (vanilloid-type) subunit OCR-2 that apparently incorporates into and inactivates OCR-2 homomers as well as heteromers with the TRPV subunits OCR-1 and -4, resulting in a premature egg-laying defect. This defect is reproduced by knocking out all three OCR genes, but not by any single knockout. Thus a mixture of redundant heteromeric channels prevents premature egg laying. These channels, as well as the G-protein Gαo, function in neuroendocrine cells to promote release of neurotransmitters that block egg laying until eggs filling the uterus deform the neuroendocrine cells. The TRPV channel OSM-9, previously suggested to be an obligate heteromeric partner of OCR-2 in sensory neurons, is expressed in the neuroendocrine cells but has no detectable role in egg laying. Our results identify a specific set of heteromeric TRPV channels that redundantly regulate neuroendocrine function and show that a subunit combination that functions in sensory neurons is also present in neuroendocrine cells but has no detectable function in these cells.
TL;DR: It is shown here that both membrane potential and the level of PI (phosphatidylinositol) phosphates are efficient regulators of TRP channel gating.
Abstract: TRP (transient receptor potential) channels respond to a plethora of stimuli in a fine-tuned manner. We show here that both membrane potential and the level of PI (phosphatidylinositol) phosphates are efficient regulators of TRP channel gating. Recent work has shown that this regulation applies to several members of the TRPV (TRP vanilloid) subfamily (TRPV1 and TRPV5) and the TRPM (TRP melastatin) subfamily (TRPM4/TRPM5/TRPM7/TRPM8), whereas regulation of members of the TRPC subfamily is still disputed. The mechanism whereby PIP(2) (PI 4,5-bisphosphate) acts on TRPM4, a Ca(2+)- and voltage-activated channel, is shown in detail in this paper: (i) PIP(2) may bind directly to the channel, (ii) PIP(2) induces sensitization to activation by Ca(2+), and (iii) PIP(2) shifts the voltage dependence towards negative and physiologically more meaningful potentials. A PIP(2)-binding pocket seems to comprise a part of the TRP domain and especially pleckstrin homology domains in the C-terminus.
TL;DR: The highly Ca(2+)-selective channel, TRPV5, contributes to several acquired mineral (dys)regulation, such as diabetes mellitus (DM), acid-base disorders, diuretics, immunosuppressant agents, and vitamin D analogues-associated Ca( 2+) imbalance whereas TRPVs may function as an osmoreceptor in kidney and participate in the regulation of sodium and water balance.
TL;DR: New findings have implicated the TRPV family of cation channels as osmo-mechanoreceptors that may mediate the neuronal responses to changes in systemic tonicity.
Abstract: For nearly 60 years, we have known that the brain plays a pivotal role in regulating the osmolality of body fluids. Over this time period, scientists have determined the structure and function of arginine vasopressin and its receptors, the role of the posterior pituitary as a storage site, and the determinants of vasopressin release. The cellular mechanisms by which the kidney responds to vasopressin are also well understood. One area that remains unclear is the neural mechanisms underlying osmoreception. New findings have implicated the TRPV family of cation channels as osmo-mechanoreceptors that may mediate the neuronal responses to changes in systemic tonicity. This topic is reviewed here.
TL;DR: In this paper, the mammalian TRPV1, 2 and 4 channels have been found to function in cellular as well as systemic osmotic homeostasis, despite not more than 26% orthology of the respective proteins.
Abstract: In signal transduction of metazoan cells, ion channels of the family of transient receptor potential (TRP) have been identified to respond to diverse external and internal stimuli, amongst them osmotic stimuli. This report highlights findings pertaining to the TRPV subfamily, focusing on mammalian members. Of the six mammalian TRPV channels, TRPV1, 2 and 4 were demonstrated to function in transduction of osmotic stimuli. TRPV channels have been found to function in cellular as well as systemic osmotic homeostasis. In a striking example of evolutionary conservation of function, mammalian TRPV4 has been found to rescue osmosensory deficits of the TRPV mutant strain osm-9 in Caenorhabditis elegans, despite not more than 26% orthology of the respective proteins.
TL;DR: Though the biological role of many of these channels in urinary bladder function still remains elusive, TRPV1 is by far the best characterized and is thought to be involved in a number of bladder disorders.
TL;DR: Results from this chapter will summarize findings on the TRPV subfamily, both its vertebrate and invertebrate members, which have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans.
Abstract: In signal transduction of metazoan cells, transient receptor potential (TRP) ion channels have been identified that respond to diverse external and internal stimuli, among them osmotic and mechanical stimuli. This chapter will summarize findings on the TRPV subfamily, both its vertebrate and invertebrate members. Of the six mammalian TRPV channels, TRPV1, -V2, and -V4 were demonstrated to function in transduction of osmotic and/or mechanical stimuli. TRPV channels have been found to function in cellular as well as systemic osmotic homeostasis in vertebrates. Invertebrate TRPV channels, five in Caenorhabditis elegans and two in Drosophila, have been shown to play a role in mechanosensation, such as hearing and proprioception in Drosophila and nose touch in C. elegans, and in the response to osmotic stimuli in C. elegans. In a striking example of evolutionary conservation of function, mammalian TRPV4 has been found to rescue mechanosensory and osmosensory deficits of the TRPV mutant line osm-9 in C. elegans, despite no more than 26% orthology of the respective amino acid sequences.
01 Jan 2007
TL;DR: For example, this article showed that the heat threshold of C-fiber mechanoheat nociceptors depends on the absolute temperature, rather than the rate of temperature increase, and that the transduction of heat stimuli occurs at different skin depths for different CMHs.
Abstract: We feel a wide range of temperatures spanning from coldness 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 (LaMotte and Campbell, 1978; Tillman et al., 1995). Neurophysiological studies have demonstrated that the heat threshold of so-called C-fiber mechanoheat nociceptors (CMHs) depends on the absolute temperature, rather than the rate of temperature increase, and that the transduction of heat stimuli occurs at different skin depths for different CMHs (Tillman et al., 1995). Extreme cold also activates a subset of nociceptive neurons. However, the physiology of cold-evoked pain is not as well understood as that of heat-evoked pain. It has been hypothesized that cutaneous nociceptor endings detect temperature and other physical stimuli by means of ion channels responsive to these stimuli. The first support for this hypothesis came from the identification of heat-gated ion channels present in a subset of primary afferent neurons (Cesare and McNaughton, 1996; Reichling and Levine, 1997). Insight into the molecular nature of these channels came shortly thereafter, with the cloning of the capsaicin receptor, TRPV1 (also known as VR1, the first member of the TRPV subfamily) and the recognition that this ion channel protein, like mammalian nociceptors, could be activated by elevated temperatures with a discrete threshold near 43°C (Caterina et al., 1997; Caterina and Julius, 2001). Three other TRPV channels—TRPV2 (also known as VRL-1), TRPV3, and TRPV4 (also known as VROAC or OTRPC4)—have been cloned and characterized as heat or warm thermosensors (Jordt et al., 2003; Patapoutian et al., 2003; Tominaga and Caterina, 2004). In addition, two TRPM channels (TRPM4 and TRPM5) have been recently reported to be thermosensitive (Talavera et al., 2005). The threshold temperatures for activation of these channels range from relatively warm (TRPV3, TRPV4, TRPM4, and TRPM5) to extremely hot (TRPV2). In contrast to these warmth- or heat-activated TRP channels, two other TRP channels—TRPM8 (also known as CMR1) and TRPA1 (also known as ANKTM1)—are activated by cold stimuli (Jordt et al., 2003; Patapoutian et al., 2003; Tominaga and Caterina, 2004). This chapter focuses on eight mammalian thermosensitive TRP channels (Figure 20.1).
TL;DR: No single TRP channel has the properties described for SOCE in platelets, so it is likely that it is composed of a heteromeric association of TRP and related subunits, some of which may be present in intracellular compartments in the resting cell.
Abstract: Ca2+ entry forms an essential component of platelet activation; however, the mechanisms associated with this process are not understood. Ca2+ entry upon receptor activation occurs as a consequence of intracellular store depletion (referred to as store-operated Ca2+ entry or SOCE), a direct action of second messengers on cation entry channels or the direct occupancy of a ligand-gated P2X1 receptor. The molecular identity of the SOCE channel has yet to be established. Transient receptor potential (TRP) proteins are candidate cation entry channels and are classified into a number of closely related subfamilies including TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin) and TRPML (mucolipins). From the TRPC family, platelets have been shown to express TRPC6 and TRPC1, and are likely to express other TRPC and other TRP members. TRPC6 is suggested to be involved with receptor-activated, diacyl-glycerol-mediated cation entry. TRPC1 has been suggested to be involved with SOCE, though many of the suggested mechanisms remain controversial. As no single TRP channel has the properties described for SOCE in platelets, it is likely that it is composed of a heteromeric association of TRP and related subunits, some of which may be present in intracellular compartments in the resting cell.
TL;DR: Two distinct aspects of TRP channel physiology, the role of TRp channels in intracellular Ca2+ homeostasis, and their role in the transduction of painful stimuli in sensory neurons are focused on.
Abstract: The transient receptor potential (TRP) channels are a large family of proteins with six main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) groups. The sheer number of different TRPs with distinct functions supports the statement that these channels are involved in a wide range of processes ranging from sensing of thermal and chemical signals to reloading intracellular stores after responding to an extracellular stimulus. Mutations in TRPs are linked to pathophysiology and specific diseases. An understanding of the role of TRPs in normal physiology is just beginning; the progression from mutations in TRPs to pathophysiology and disease will follow. In this review, we focus on two distinct aspects of TRP channel physiology, the role of TRP channels in intracellular Ca2+ homeostasis, and their role in the transduction of painful stimuli in sensory neurons