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Results for “Transient Receptor Potential Channels”

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At least 397 records · Page 22Linked to original sources
PubMed2004

TRPA1 is a candidate for the mechanosensitive transduction channel of vertebrate hair cells.

Mechanical deflection of the sensory hair bundles of receptor cells in the inner ear causes ion channels located at the tips of the bundle to open, thereby initiating the perception of sound. Although some protein constituents of the transduction apparatus are known, the mechanically gated transduction channels have not been identified in higher vertebrates. Here, we investigate TRP (transient receptor potential) ion channels as candidates and find one, TRPA1 (also known as ANKTM1), that meets criteria for the transduction channel. The appearance of TRPA1 messenger RNA expression in hair cell epithelia coincides developmentally with the onset of mechanosensitivity. Antibodies to TRPA1 label hair bundles, especially at their tips, and tip labelling disappears when the transduction apparatus is chemically disrupted. Inhibition of TRPA1 protein expression in zebrafish and mouse inner ears inhibits receptor cell function, as assessed with electrical recording and with accumulation of a channel-permeant fluorescent dye. TRPA1 is probably a component of the transduction channel itself.

Adenoviridae↗
PubMed2007

The TRP channel superfamily: insights into how structure, protein-lipid interactions and localization influence function.

TRP (transient receptor potential) cationic channels are key molecules that are involved in a variety of diverse biological processes ranging from fertility to osmosensation and nociception. Increasing our knowledge of these channels will help us to understand a range of physiological and pathogenic processes, as well as highlighting potential therapeutic drug targets. The founding members of the TRP family, Drosophila TRP and TRPL (TRP-like) proteins, were identified within the last two decades and there has been a subsequent explosion in the number and type of TRP channel described. Although information is accumulating as to the function of some of the TRP channels, the activation and inactivation mechanisms, structure, and interacting proteins of many, if not most, are awaiting elucidation. The Cell and Molecular Biology of TRP Channels Meeting held at the University of Bath included speakers working on a number of the different subfamilies of TRP channels and provided a basis for highlighting both similarities and differences between these groups. As the TRP channels mediate diverse functions, this meeting also brought together an audience with wide-ranging research interests, including biochemistry, cell biology, physiology and neuroscience, and inspired lively discussion on the issues reviewed herein.

Animals↗
PubMed2006

Zinc and copper: pharmacological probes and endogenous modulators of neuronal excitability.

As well as being key structural components of many proteins, increasing evidence suggests that zinc and copper ions function as signaling molecules in the nervous system and are released from the synaptic terminals of certain neurons. In this review, we consider the actions of these two ions on proteins that regulate neuronal excitability. In addition to the established actions of zinc, and to a lesser degree copper, on excitatory and inhibitory ligand-gated ion channels, we show that both ions have a number of actions on selected members of the voltage-gated-like ion channel superfamily. For example, zinc is a much more effective blocker of one subtype of tetrodotoxin (TTX)-insensitive sodium (Na+) channel (NaV1.5) than other Na+ channels, whereas a certain T-type calcium (Ca2+) channel subunit (CaV3.2) is particularly sensitive to zinc. For potassium (K+) channels, zinc can have profound effects on the gating of certain KV channels whereas zinc and copper have distinct actions on closely related members of the 2 pore domain potassium channel (K2P) channel family. In addition to direct actions on these proteins, zinc is able to permeate a number of membrane proteins such as (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate receptors, Ca2+ channels and some transient receptor potential (trp) channels. There are a number of important physiological and pathophysiological consequences of these many actions of zinc and copper on membrane proteins, in terms of regulation of neuronal excitability and neurotoxicity. Furthermore, the concentration of free zinc and copper either in the synaptic cleft or neuronal cytoplasm may contribute to the etiology of certain disease states such as Alzheimer's disease (AD) and epilepsy.

Alzheimer Disease↗
PubMed2004

Functional TRPV4 channels are expressed in human airway smooth muscle cells.

Hypotonic stimulation induces airway constriction in normal and asthmatic airways. However, the osmolarity sensor in the airway has not been characterized. TRPV4 (also known as VR-OAC, VRL-2, TRP12, OTRPC4), an osmotic-sensitive cation channel in the transient receptor potential (TRP) channel family, was recently cloned. In the present study, we show that TRPV4 mRNA was expressed in cultured human airway smooth muscle cells as analyzed by RT-PCR. Hypotonic stimulation induced Ca(2+) influx in human airway smooth muscle cells in an osmolarity-dependent manner, consistent with the reported biological activity of TRPV4 in transfected cells. In cultured muscle cells, 4alpha-phorbol 12,13-didecanoate (4-alphaPDD), a TRPV4 ligand, increased intracellular Ca(2+) level only when Ca(2+) was present in the extracellular solution. The 4-alphaPDD-induced Ca(2+) response was inhibited by ruthenium red (1 microM), a known TRPV4 inhibitor, but not by capsazepine (1 microM), a TRPV1 antagonist, indicating that 4-alphaPDD-induced Ca(2+) response is mediated by TRPV4. Verapamil (10 microM), an L-type voltage-gated Ca(2+) channel inhibitor, had no effect on the 4-alphaPDD-induced Ca(2+) response, excluding the involvement of L-type Ca(2+) channels. Furthermore, hypotonic stimulation elicited smooth muscle contraction through a mechanism dependent on membrane Ca(2+) channels in both isolated human and guinea pig airways. Hypotonicity-induced airway contraction was not inhibited by the L-type Ca(2+) channel inhibitor nifedipine (1 microM) or by the TRPV1 inhibitor capsazepine (1 microM). We conclude that functional TRPV4 is expressed in human airway smooth muscle cells and may act as an osmolarity sensor in the airway.

Animals↗
PubMed2004

Cutting edge: optical microspectrophotometry supports the existence of gel phase lipid rafts at the lamellipodium of neutrophils: apparent role in calcium signaling.

Although much progress has been made in elucidating the biochemical properties of lipid rafts, there has been less success in identifying these structures within living cell membranes, which has led to some concern regarding their existence. One difficulty in analyzing lipid rafts using optical microscopy is their small size. We now test the existence of lipid rafts in polarized neutrophils, which redistribute lipid raft markers into comparatively large lamellipodia. Optical microspectrophotometry of Laurdan-labeled neutrophils revealed a large blue shift at lamellipodia relative to cell bodies. This blue shift disappeared after exposure to methyl-beta-cyclodextrin (m beta CD), which disrupts lipid rafts. The Ca(2+) channel transient receptor potential-like channel-1, a lipid raft marker, traffics to lamellipodia, but redistributes uniformly about cells after exposure to m beta CD. This is accompanied by disruption of Ca(2+) waves normally initiated at lamellipodia. Thus, m beta CD-sensitive lipid-ordered domains are present at and participate in signaling from the lamellipodia of living neutrophils.

Biomarkers↗
PubMed2006

TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction.

TRPA1, a member of the transient receptor potential (TRP) family of ion channels, is expressed by dorsal root ganglion neurons and by cells of the inner ear, where it has proposed roles in sensing sound, painful cold, and irritating chemicals. To test the in vivo roles of TRPA1, we generated a mouse in which the essential exons required for proper function of the Trpa1 gene were deleted. Knockout mice display behavioral deficits in response to mustard oil, to cold ( approximately 0 degrees C), and to punctate mechanical stimuli. These mice have a normal startle reflex to loud noise, a normal sense of balance, a normal auditory brainstem response, and normal transduction currents in vestibular hair cells. TRPA1 is apparently not essential for hair-cell transduction but contributes to the transduction of mechanical, cold, and chemical stimuli in nociceptor sensory neurons.

Animals↗
PubMed2005

TRPV4 as osmosensor: a transgenic approach.

The transient receptor potential vanilloid 4 (TRPV4) ion channel was named initially vanilloid-receptor-related osmotically activated channel (VR-OAC). Preliminary answers to the question, "What is the function of the trpv4 gene in live animals ?" are highlighted briefly in this review. In trpv4 null mice, TRPV4 is necessary for the maintenance of osmotic equilibrium, and in Caenorhabditis elegans transgenic for mammalian TRPV4, TRPV4 directs the osmotic avoidance response in the context of the ASH "nociceptive" neuron. The molecular mechanisms of gating of TRPV4 in vivo need to be determined; in particular, whether TRPV4 in live animals is gated via phosphorylation of defined amino-acid residues or more directly through the osmotic stimulus itself.

Animals↗
PubMed2005

The TRP superfamily of cation channels.

The transient receptor potential (TRP) protein superfamily consists of a diverse group of cation channels that bear structural similarities to Drosophila TRP. TRP channels play important roles in nonexcitable cells; however, an emerging theme is that many TRP-related proteins are expressed predominantly in the nervous system and function in sensory physiology. The TRP superfamily is divided into seven subfamilies, the first of which is composed of the "classical" TRPs" (TRPC subfamily). Some TRPCs may be store-operated channels, whereas others appear to be activated by production of diacylglycerol or regulated through an exocytotic mechanism. Many members of a second subfamily (TRPV) function in sensory physiology and respond to heat, changes in osmolarity, odorants, and mechanical stimuli. Two members of the TRPM family function in sensory perception and three TRPM proteins are chanzymes, which contain C-terminal enzyme domains. The fourth and fifth subfamilies, TRPN and TRPA, include proteins with many ankyrin repeats. TRPN proteins function in mechanotransduction, whereas TRPA1 is activated by noxious cold and is also required for the auditory response. In addition to these five closely related TRP subfamilies, which comprise the Group 1 TRPs, members of the two Group 2 TRP subfamilies, TRPP and TRPML, are distantly related to the group 1 TRPs. Mutations in the founding members of these latter subfamilies are responsible for human diseases. Each of the TRP subfamilies are represented by members in worms and flies, providing the potential for using genetic approaches to characterize the normal functions and activation mechanisms of these channels.

Amino Acid Sequence↗
PubMed2002

mRNA distribution analysis of human TRPC family in CNS and peripheral tissues.

The mammalian homologues of the Drosophila transient receptor potential (TRP) channel are plasma membrane proteins involved in the regulation of cellular Ca(2+) influx. These ion channels can be activated subsequent to either depletion of Ca(2+) from internal stores or through receptor-mediated processes. The mRNA expression patterns of several individual mammalian short transient receptor potential channels (TRPCs) have been described. Cross-comparisons between these data, however, are at best difficult predominantly due to the non-quantitative methods used. Furthermore there is limited data on the expression of TRPC family members in human tissues. In the present study we used a single technique, namely TaqMan real-time quantitative RT-PCR, to investigate the mRNA distribution of human TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7 (hTRPCs) in discrete human brain areas, peripheral tissues as well as a panel of cell-lines. All hTRPCs studied were widely expressed within CNS and significant peripheral expression was often observed. Despite this, each channel exhibited a distinctive hallmark distribution profile. hTRPC1 was widely expressed in CNS and peripheral tissues, whereas hTRPC3 and hTRPC5 were predominantly expressed in tissues of CNS. hTRPC4 mRNA was detected in CNS and certain peripheral tissues such as bone, heart and prostate. hTRPC6 was homogeneously expressed throughout the CNS and peripheral tissues with the highest levels in placenta and lung. hTRPC7 mRNA was also broadly expressed in CNS as well as some peripheral tissues. The pattern of expression of the TRPCs was quite different in the various cell lines examined. TRPC3 and TRPC6 were selectively present in HEK-293 cells whilst TRPC1 was broadly distributed in the cell lines analyzed. In contrast TRPC4 and TRPC5 mRNAs were predominantly expressed in HK-2 and HEK-293 cell lines respectively. TRPC7 was selectively expressed in COS-1, COS-7 and HK-2 cell lines. These results show tissue- and cell-specific co-expression of multiple TRPC forms indicating widespread potential for formation of heteromeric channels. These data will be useful in the complex task of relating channel subunit composition to function in native cells.

Animals↗
PubMed2005

Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism.

Camphor is a naturally occurring compound that is used as a major active ingredient of balms and liniments supplied as topical analgesics. Despite its long history of common medical use, the underlying molecular mechanism of camphor action is not understood. Capsaicin and menthol, two other topically applied agents widely used for similar purposes, are known to excite and desensitize sensory nerves by acting on two members of transient receptor potential (TRP) channel superfamily: heat-sensitive TRP vanilloid subtype 1 (TRPV1) and cold-sensitive TRP channel M8, respectively. Camphor has recently been shown to activate TRPV3, and here we show that camphor also activates heterologously expressed TRPV1, requiring higher concentrations than capsaicin. Activation was enhanced by phospholipase C-coupled receptor stimulation mimicking inflamed conditions. Similar camphor-activated TRPV1-like currents were observed in isolated rat DRG neurons and were strongly potentiated after activation of protein kinase C with phorbol-12-myristate-13-acetate. Camphor activation of rat TRPV1 was mediated by distinct channel regions from capsaicin, as indicated by camphor activation in the presence of the competitive inhibitor capsazepine and in a capsaicin-insensitive point mutant. Camphor did not activate the capsaicin-insensitive chicken TRPV1. TRPV1 desensitization is believed to contribute to the analgesic actions of capsaicin. We found that, although camphor activates TRPV1 less effectively, camphor application desensitized TRPV1 more rapidly and completely than capsaicin. Conversely, TRPV3 current sensitized after repeated camphor applications, which is inconsistent with the analgesic role of camphor. We also found that camphor inhibited several other related TRP channels, including ankyrin-repeat TRP 1 (TRPA1). The camphor-induced desensitization of TRPV1 and block of TRPA1 may underlie the analgesic effects of camphor.

Animals↗
PubMed2006

Specification of auditory sensitivity by Drosophila TRP channels.

Ears achieve their exquisite sensitivity by means of mechanical feedback: motile mechanosensory cells through their active motion boost the mechanical input from the ear. Examination of the auditory mechanics in Drosophila melanogaster mutants shows that the transient receptor potential (TRP) channel NompC is required to promote this feedback, whereas the TRP vanilloid (TRPV) channels Nan and Iav serve to control the feedback gain. The combined function of these channels specifies the sensitivity of the fly auditory organ.

Animals↗
PubMed2002

Endogenously expressed Trp1 is involved in store-mediated Ca2+ entry by conformational coupling in human platelets.

Physical interaction between transient receptor potential (Trp) channels and inositol 1,4,5-trisphosphate receptors (IP(3)Rs) has been presented as a candidate mechanism for the activation of store-mediated Ca(2+) entry. The role of a human homologue of Drosophila transient receptor potential channel, hTrp1, in the conduction of store-mediated Ca(2+) entry was examined in human platelets. Incubation of platelets with a specific antibody, which recognizes the extracellular amino acid sequence 557-571 of hTrp1, inhibited both store depletion-induced Ca(2+) and Mn(2+) entry in a concentration-dependent manner. Stimulation of platelets with the physiological agonist thrombin activated coupling between the IP(3) receptor type II and endogenously expressed hTrp1. This event was reversed by refilling of the internal Ca(2+) stores but maintained after removal of the agonist if the stores were not allowed to refill. Inhibition of IP(3) recycling using Li(+) or inhibition of IP(3)Rs with xestospongin C or treatment with jasplakinolide, to stabilize the cortical actin filament network, abolished thrombin-induced coupling between hTrp1 and IP(3)R type II. Incubation with the anti-hTrp1 antibody inhibited thrombin-evoked Ca(2+) entry without affecting Ca(2+) release from intracellular stores. These results provide evidence for the involvement of hTrp1 in the activation of store-mediated Ca(2+) entry by coupling to IP(3)R type II in normal human cells.

Amino Acid Sequence↗
PubMed2005

The role of TRPM channels in cell death.

Transient receptor potential (TRP) channels of the melastatin-like family (TRPM) play critical roles in mediating cellular responses to a wide range of physiological stimuli that, under certain situations, can induce cell death. To date, two TRPM family members, TRPM2 and TRPM7, have been implicated directly as central components of cell death pathways. TRPM2, a Ca(2+)-permeant, non-selective cation channel, senses and responds to oxidative stress levels in the cell. TRPM7 is required for cell viability and has been proposed recently to mediate stress-induced cell death in the central nervous system. We review here the evidence for the involvement of these TRPM channels in cell death processes and discuss the mechanisms by which TRPM channel activation occurs. The ability to attenuate expression levels and functionality of these channels is necessary to understand the involvement of TRPM in cell death and we evaluate current approaches for modulation of TRPM channel function. Finally, we discuss the possibility that TRPM channels may provide therapeutic targets for degenerative diseases involving oxidative stress-related pathologies including diabetes and Alzheimer's disease.

Animals↗
PubMed2006

Regulation of TRP channels by PIP(2).

Transient receptor potential (TRP) channels are regulated by a wide variety of physical and chemical factors. Recently, several members of the TRP channel family were reported to be regulated by phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2), PIP(2)). This review will summarize the current knowledge on PIP(2) regulation of TRP channels and discuss the possibility that PIP(2) is a common regulator of mammalian TRP channels.

Animals↗
PubMed2006

Different expression patterns of TRP genes in murine B and T lymphocytes.

A prolonged increase in the intracellular calcium concentration ([Ca2+]i) is essential for lymphocyte activation that includes cell proliferation and differentiation. This increase in [Ca2+]i results from Ca2+ release from the intracellular store and the subsequent Ca2+ influx from the extracellular environment via calcium channels located on the plasma membrane. Although transient receptor potential (TRP) channels have been reported to play important roles in the [Ca2+]i increase in lymphocytes, the function of these channels in lymphocyte activation remains unknown. Here, we report the comprehensive expression profile of TRP channel gene families including TRPC, TRPV, and TRPM in the murine immune system. RT-PCR analysis revealed different expression patterns of the TRP channel genes in B and T lymphocytes isolated from the spleen. Therefore, our results provide an appropriate reference of TRP gene expression in murine lymphocytes.

Animals↗
PubMed2004

The role of TRP channels in sensory neurons.

Two parallel processes characterize the contemporary pain field. Firstly, enormous progress is being made in the discovery of the cellular and molecular mechanisms responsible for the pathogenesis of pain and secondly, there is a growing appreciation that multiple mechanisms contribute to common clinical pain syndromes. The aim of this chapter is to provide a short overview how transient receptor potential (TRP) channels could contribute to acute and chronic pain states. TRP channels of the vanilloid family (TRPV1, TRPV2, TRPV3, TRPV4) are excited by heat stimuli whereas TRPM8 and ANKTM1 are cold responsive. TRPV1 and ANKTM1 are mediating the pungency of nociceptor-specific chemicals such as capsaicin or mustard oil. Sensitization of TRPV1 is an important mechanisms for heat hyperalgesia and thus the generation of chronic pain symptoms.

Arthralgia↗
PubMed2005

Cation channel activity of mucolipin-1: the effect of calcium.

Mucolipidosis type IV (MLIV) is a rare, neurogenetic disorder characterized by developmental abnormalities of the brain, and impaired neurological, ophthalmological, and gastric function. Considered a lysosomal disease, MLIV is characterized by the accumulation of large vacuoles in various cell types. Recent evidence indicates that MLIV is caused by mutations in MCOLN1, the gene that encodes mucolipin-1 (ML1), a 65-kDa protein showing sequence homology and topological similarities with polycystin-2 and other transient receptor potential (TRP) channels. In this report, our observations on the channel properties of ML1, and molecular pathophysiology of MLIV are reviewed and expanded. Our studies have shown that ML1 is a multiple sub-conductance, non-selective cation channel. MLIV-causing mutations result in functional differences in the channel protein. In particular, the V446L and DeltaF408 mutations retain channel function but have interesting functional differences with regards to pH dependence and Ca(2+) transport. While the wild-type protein is inhibited by Ca(2+) transport, mutant ML1 is not. Atomic force microscopy imaging of ML1 channels shows that changes in pH modify the aggregation and size of the ML1 channels, which has an impact on vesicular fusogenesis. The new evidence provides support for a novel role of ML1 cation channels in vesicular acidification and normal endosomal function.

Amino Acid Sequence↗
PubMed2001

Regulation of Drosophila transient receptor potential-like (TrpL) channels by phospholipase C-dependent mechanisms.

Patch clamp and fura-2 fluorescence were employed to characterize receptor-mediated activation of recombinant Drosophila TrpL channels expressed in Sf9 insect cells. TrpL was activated by receptor stimulation and by exogenous application of diacylglycerol (DAG) or poly-unsaturated fatty acids (PUFAs). Activation of TrpL was blocked more than 70% by U73122, suggesting that the effect of these agents was dependent upon phospholipase C (PLC). In fura-2 assays, extracellular application of bacterial phosphatidylinositol (PI)-PLC or phosphatidylcholine (PC)-PLC caused a transient increase in TrpL channel activity, the magnitude of which was significantly less than that observed following receptor stimulation. TrpL channels were also activated in excised inside-out patches by cytoplasmic application of mammalian PLC-b2, bacterial PI-PLC and PC-PLC, but not by phospholipase D (PLD). The phospholipases had little or no effect when examined in either whole-cell or cell-attached configurations.TrpL activity was inhibited by addition of phosphatidylinositol-4,5-bisphosphate (PIP2) to excised inside-out membrane patches exhibiting spontaneous channel activity or to patches pre-activated by treatment with PLC. The effect was reversible, specific for PIP2, and was not observed with phosphatidylethanolamine (PE), PI, PC or phosphatidylserine (PS). However, antibodies against PIP2 consistently failed to activate TrpL in inside-out patches. It is concluded that both the hydrolysis of PIP2 and the generation of DAG are required to rapidly activate TrpL following receptor stimulation, or that some other PLC-dependent mechanism plays a crucial role in the activation process.

Animals↗