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PubMed2007

Open channel block by Ca2+ underlies the voltage dependence of drosophila TRPL channel.

The light-activated channels of Drosophila photoreceptors transient receptor potential (TRP) and TRP-like (TRPL) show voltage-dependent conductance during illumination. Recent studies implied that mammalian members of the TRP family, which belong to the TRPV and TRPM subfamilies, are intrinsically voltage-gated channels. However, it is unclear whether the Drosophila TRPs, which belong to the TRPC subfamily, share the same voltage-dependent gating mechanism. Exploring the voltage dependence of Drosophila TRPL expressed in S2 cells, we found that the voltage dependence of this channel is not an intrinsic property since it became linear upon removal of divalent cations. We further found that Ca(2+) blocked TRPL in a voltage-dependent manner by an open channel block mechanism, which determines the frequency of channel openings and constitutes the sole parameter that underlies its voltage dependence. Whole cell recordings from a Drosophila mutant expressing only TRPL indicated that Ca(2+) block also accounts for the voltage dependence of the native TRPL channels. The open channel block by Ca(2+) that we characterized is a useful mechanism to improve the signal to noise ratio of the response to intense light when virtually all the large conductance TRPL channels are blocked and only the low conductance TRP channels with lower Ca(2+) affinity are active.

Animals↗
PubMed2007

Regulation of calcium signalling by adenine-based second messengers.

cADPR [cyclic ADPR (ADP-ribose)], NAADP (nicotinic acid-adenine dinucleotide phosphate) and ADPR belong to the family of adenine-containing second messengers. They are metabolically related and are all involved in the regulation of cellular Ca(2+) homoeostasis. Activation of specific plasma membrane receptors is connected to cADPR formation in many cell types and tissues. In contrast receptor-mediated formation of NAADP and ADPR has been shown only in a few selected cellular systems. The intracellular Ca(2+) channel triggered by cADPR is the RyR (ryanodine receptor); in the case of NAADP, both activation of RyR and a novel Ca(2+) channel have been proposed. In contrast, ADPR opens the non-specific cation channel TRPM2 [TRP (transient receptor potential) melastatin 2] that belongs to the TRP family of ion channels.

Adenine↗
PubMed2002

Metabotropic glutamate receptor 5 and calcium signaling in retinal amacrine cells.

To begin to understand the modulatory role of glutamate in the inner retina, we examined the mechanisms underlying metabotropic glutamate receptor 5 (mGluR5)-dependent Ca(2+) elevations in cultured GABAergic amacrine cells. A partial sequence of chicken retinal mGluR5 encompassing intracellular loops 2 and 3 suggests that it can couple to both G(q) and G(s). Selective activation of mGluR5 stimulated Ca(2+) elevations that varied in waveform from cell to cell. Experiments using high external K(+) revealed that the mGluR5-dependent Ca(2+) elevations are distinctive in amplitude and time course from those engendered by depolarization. Experiments with a Ca(2+) -free external solution demonstrated that the variability in the time course of mGluR5-dependent Ca(2+) elevations is largely due to the influx of extracellular Ca(2+). The sensitivity of the initial phase of the Ca(2+) elevation to thapsigargin indicates that this phase of the response is due to the release of Ca(2+) from the endoplasmic reticulum. Pharmacological evidence indicates that mGluR5-mediated Ca(2+) elevations are dependent upon the activation of phospholipase C. We rule out a role for L-type Ca(2+) channels and cAMP-gated channels as pathways for Ca(2+) entry, but provide evidence of transient receptor potential (TRP) channel-like immunoreactivity, suggesting that Ca(2+) influx may occur through TRP channels. These results indicate that GABAergic amacrine cells express an avian version of mGluR5 that is linked to phospholipase C-dependent Ca(2+) release and Ca(2+) influx, possibly through TRP channels.

Amacrine Cells↗
PubMed2005

Localization of TRPC1 channel in the sinus endothelial cells of rat spleen.

The ultrastructural localization of transient receptor potential C1 (TRPC1) channels in the sinus endothelial cells of rat spleen was examined by confocal laser scanning and electron microscopy. In addition, the localization of the closely associated proteins and channels, VE-cadherin, calreticulin, inositol-1,4,5-trisphosphate receptors type 1 (IP3R1), and ryanodine receptor (RyR), was also examined. Immunofluorescence microscopy of tissue cryosections revealed TRPC1 channels to be localized within the cytoplasm, in the superficial layer of the apical and basal parts of the cells, and in the junctional area of the adjacent endothelial cells. The distribution of Ca2+-storing tubulovesicular structures within endothelial cells was established by using tissue sections treated with osmium ferricyanide. Electron microscopy revealed densely stained tubulovesicular structures closely apposed to the plasma membrane and that occasionally ran closely parallel to the plasma membrane and near the caveolae and junctional apparatus. Immunolocalization analysis at the electron microscopy level using immunogold bound to the secondary antibody confirmed that TRPC1 channels were localized in the plasma membrane, caveolae, and vesicular structures in the subplasmalemmal cytoplasm of sinus endothelial cells. Calreticulin was predominantly localized in endoplasmic reticulum. IP3R1 and RyR, considered to be type 3, were colocalized in endoplasmic reticulum in proximity to the plasma membrane and caveolae. Thus, TRPC1 channels in sinus endothelial cells of the spleen might play an important role in controlling blood cell passage through phenomena including cytoskeletal reorganization, cell retraction, and disassembly of adherens junctions.

Animals↗
PubMed2004

Protein kinase Calpha phosphorylates the TRPC1 channel and regulates store-operated Ca2+ entry in endothelial cells.

The TRPC1 (transient receptor potential canonical-1) channel is a constituent of the nonselective cation channel that mediates Ca2+ entry through store-operated channels (SOCs) in human endothelial cells. We investigated the role of protein kinase Calpha (PKCalpha) phosphorylation of TRPC1 in regulating the opening of SOCs. Thrombin or thapsigargin added to the external medium activated Ca2+ entry after Ca2+ store depletion, which we monitored by changes in cellular Fura 2 fluorescence. Internal application of the metabolism-resistant analog of inositol 1,4,5-trisphosphate (IP3) activated an inward cationic current within 1 min, which we recorded using the whole cell patch clamp technique. La3+ or Gd3+ abolished the current, consistent with the known properties of SOCs. Pharmacological (Gö6976) or genetic (kinase-defective mutant) inhibition of PKCalpha markedly inhibited IP3-induced activation of the current. Thrombin or thapsigargin also activated La3+-sensitive Ca2+ entry in a PKCalpha-dependent manner. We determined the effects of a specific antibody directed against an extracellular epitope of TRPC1 to address the functional importance of TRPC1. External application of the antibody blocked thrombin- or IP3-induced Ca2+ entry. In addition, we showed that addithrombin or thapsigargin induced phosphorylation of TRPC1 within 1 min. Thrombin failed to induce TRPC1 phosphorylation in the absence of PKCalpha activation. Phosphorylation of TRPC1 and the resulting Ca2+ entry were essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. These results demonstrate that PKCalpha phosphorylation of TRPC1 is an important determinant of Ca2+ entry in human endothelial cells.

Antibodies↗
PubMed2007

TRPC1: a core component of store-operated calcium channels.

The TRPC (transient receptor potential canonical) proteins are activated in response to agonist-stimulated PIP(2) (phosphatidylinositol 4,5-bisphosphate) hydrolysis and have been suggested as candidate components of the elusive SOC (store-operated calcium channel). TRPC1 is currently the strongest candidate component of SOC. Endogenous TRPC1 has been shown to contribute to SOCE (store-operated calcium entry) in several different cell types. However, the mechanisms involved in the regulation of TRPC1 and its exact physiological function have yet to be established. Studies from our laboratory and several others have demonstrated that TRPC1 is assembled in a signalling complex with key calcium signalling proteins in functionally specific plasma membrane microdomains. Furthermore, critical interactions between TRPC1 monomers as well as interactions between TRPC1 and other proteins determine the surface expression and function of TRPC1-containing channels. Recent studies have revealed novel regulators of TRPC1-containing SOCs and have demonstrated a common molecular basis for the regulation of CRAC (calcium-release-activated calcium) and SOC channels. In the present paper, we will revisit the role of TRPC1 in SOCE and discuss how studies with TRPC1 provide an experimental basis for validating the mechanism of SOCE.

Animals↗
PubMed2005

Interplay between P2Y(1), P2Y(12), and P2X(1) receptors in the activation of megakaryocyte cation influx currents by ADP: evidence that the primary megakaryocyte represents a fully functional model of platelet P2 receptor signaling.

The difficulty of conducting electrophysiologic recordings from the platelet has restricted investigations into the role of ion channels in thrombosis and hemostasis. We now demonstrate that the well-established synergy between P2Y(1) and P2Y(12) receptors during adenosine diphosphate (ADP)-dependent activation of the platelet alpha(IIb)beta(3) integrin also exists in murine marrow megakaryocytes, further supporting the progenitor cell as a bona fide model of platelet P2 receptor signaling. In patch clamp recordings, ADP (30 microM) stimulated a transient inward current at -70 mV, which was carried by Na(+) and Ca(2+) and was amplified by phenylarsine oxide, a potentiator of certain transient receptor potential (TRP) ion channels by phosphatidylinositol 4,5-bisphosphate depletion. This initial current decayed to a sustained phase, upon which repetitive transient inward cation currents with pre-dominantly P2X(1)-like kinetics were super-imposed. Abolishing P2X(1)-receptor activity prevented most of the repetitive currents, consistent with their activation by secreted adenosine triphosphate (ATP). Recordings in P2Y(1)-receptor-deficient megakaryocytes demonstrated an essential requirement of this receptor for activation of all ADP-evoked inward currents. However, P2Y(12) receptors, through the activation of PI3-kinase, played a synergistic role in both P2Y(1) and P2X(1)-receptor-dependent currents. Thus, direct stimulation of P2Y(1) and P2Y(12) receptors, together with autocrine P2X(1) activation, is responsible for the activation of nonselective cation currents by the platelet agonist ADP.

Adenosine Diphosphate Ribose↗
PubMed2006

Evolution of thermoTRP ion channel homologs in vertebrates.

In mammalian thermosensation, nine temperature-sensitive ion channels that are activated by distinct temperature thresholds have been identified as thermosensors. These ion channels belong to the transient receptor potential (TRP) superfamily and are referred to as "thermoTRPs" (TRPV1, TRPV2, TRPV3, TRPV4, TRPM2, TRPM4, TRPM5, TRPM8, and TRPA1). To elucidate the evolutionary processes of thermoTRPs, we conducted comprehensive searches for mammalian thermoTRP gene homologs in the draft genome sequences of chicken (Gallus gallus), western clawed frog (Xenopus tropicalis), zebrafish (Danio rerio), and pufferfish (Fugu rubripes). Newly identified homologs were compared with known thermoTRPs, and phylogenetic analyses were conducted. Our comparative analyses revealed that most of the mammalian thermo-TRP members already existed in the common ancestor of fishes and tetrapods. Tetrapods shared almost the same repertoire, except that the western clawed frog expanded TRPV4s (six copies) and TRPM8s (two copies), which were diversified considerably. Comparisons of nonsynonymous and synonymous substitution rates among TRPV4s suggested that one copy of the TRPV4 channel in the western clawed frog retained its original function, while the other copies diversified and obtained slightly different properties. In fish lineages, several members of thermo-TRPs have duplicated in the whole genome duplication occurred in the ancestral ray-finned fish; however, some of the copies have subsequently been lost. Furthermore, fishes do not possess the three members of thermoTRPs existed in mammals, e.g., thermoTRPs activated by noxious heat, warm, and cool temperatures. Our results suggest that thermosensation mechanisms have changed through vertebrate evolution with respect to thermosensor repertoires.

Animals↗
PubMed2006

Trp ion channels and temperature sensation.

The abilities to sense environmental and internal temperatures are required for survival, both for maintenance of homeostasis and for avoidance of tissue-damaging noxious temperatures. Vertebrates can sense external physical stimuli via specialized classes of neurons in the peripheral nervous system that project to the skin. Temperature-sensitive neurons can be divided into two classes: innocuous thermosensors (warm or cool) and noxious thermonociceptors (hot or cold). ThermoTRPs, a subset of the transient receptor potential family of ion channels, which are expressed in sensory nerve endings and in skin, respond to distinct thermal thresholds. In this review, we examine the extent to which thermoTRPs are responsible for providing a molecular basis for thermal sensation.

Animals↗
PubMed2006

Functional expression of transient receptor potential vanilloid 4 in the mouse cochlea.

Transient receptor potential vanilloid 4, the Ca2+-permeable cation channel has been proposed as an osmosensitive and a mechanosensitive channel. We investigated functional expression of transient receptor potential vanilloid 4 in inner hair cells, outer hair cells, and spiral ganglion neurons of the mouse cochlea. Transient receptor potential vanilloid 4 mRNA and protein were expressed in inner hair cells, outer hair cells, and spiral ganglion neurons on the basis of the findings of reverse transcriptase-polymerase chain reaction, single-cell reverse transcriptase-polymerase chain reaction, and immunohistochemistry, whereas they were negative in transient receptor potential vanilloid 4-/- mice cochleae. Hypotonic stimulation and 4-alpha-phorbol 12,13-didecanoate, a transient receptor potential vanilloid 4 synthetic activator, increased the intracellular Ca2+ concentrations in wild-type outer hair cells, whereas in transient receptor potential vanilloid 4-/- mice, outer hair cells failed to exhibit a Ca2+ response to both stimulations. In conclusion, transient receptor potential vanilloid 4 may function as an osmosensory and a mechanosensory receptor in the cochlea.

Animals↗
PubMed2005

Protein-protein interaction and functionTRPC channels.

Since their identification in the concluding years of the last century, the mammalian transient receptor potential (canonical) (TRPC) channels have remained in the limelight as the primary candidates for the Ca(2+) entry pathway activated by the hormones, growth factors, and neurotransmitters that exert their effect through activation of PLC. Although TRPC channels have been shown clearly to mediate, at least in part, receptor-activated Ca(2+) entry in literally all cell types, several of their central characteristics, as recorded in expression systems using recombinant channels, differ from those of the native receptor-dependent Ca(2+) influx channels. The present review attempts to highlight the interaction of TRPC channels with other proteins, which may explain the variability of TRPC channel activation and regulatory mechanisms observed with the native and recombinant channels. These include the homologous and heterotopous interactions of TRPC channel isoforms, the interaction of TRPC channels with calmodulin, PLCgamma, IP(3) receptors, and with scaffolding proteins like InaD, EBP50/NEHRF, caveolin, Janctate and Homers.

Animals↗
PubMed2006

Permeation and selectivity of TRP channels.

Ion channels are pore-forming transmembrane proteins that allow ions to permeate biological membranes. Pore structure plays a crucial role in determining the ion permeation and selectivity properties of particular channels. In the past few decades, efforts have been undertaken to identify key elements of the pore regions of different classes of ion channels. In this review, we summarize current knowledge about permeation and selectivity of channel proteins from the transient receptor potential (TRP) superfamily. Whereas all TRP channels are permeable for cations, only two TRP channels are impermeable for Ca2+ (TRPM4, TRPM5), and two others are highly Ca2+ permeable (TRPV5, TRPV6). Despite the great advances in the TRP channel field during the past decade, only a limited number of reports have dealt with functional characterization of pore properties, biophysical aspects of cation permeation, or description of pore structures of TRP channels. This review gives an overview of available experimental and theoretical data and discusses the functional impact of pore-structure modifications on TRP channel properties.

Algorithms↗
PubMed2005

Induction of intracellular calcium elevation by Delta9-tetrahydrocannabinol in T cells involves TRPC1 channels.

We have reported previously that Delta9-tetrahydrocannabinol (Delta9-THC) treatment of resting human and murine splenic T cells robustly elevated intracellular calcium ([Ca2+]i). The objective of the present investigation was to examine the putative role of [Ca2+]i store depletion and store-operated calcium (SOC) and receptor-operated cation (ROC) channels in the mechanism by which Delta9-THC increases [Ca2+]i in the cannabinoid-2 receptor-expressing human peripheral blood-acute lymphoid leukemia (HPB-ALL) human T cell line. By using the smooth endoplasmic reticulum Ca2+-ATPase pump inhibitor, thapsigargin, and the ryanodine receptor antagonist, 8-bromo-cyclic adenosine diphosphate ribose, we demonstrate that the Delta9-THC-mediated elevation in [Ca2+]i occurs independently of [Ca2+]i store depletion. Furthermore, the ROC channel inhibitor, SK&F 96365 was more efficacious at attenuating the Delta9-THC-mediated elevation in [Ca2+]i than SOC channel inhibitors, 2-aminoethoxydiphenyl borate and La3+. Recently, several members of the transient receptor potential canonical (TRPC) channel subfamily have been suggested to operate as SOC or ROC channels. In the present studies, treatment of HPB-ALL cells with 1-oleoyl-2-acetyl-sn-glycerol (OAG), a cell-permeant analog of diacylglycerol (DAG), which gates several members of the TRPC channel subfamily, rapidly elevated [Ca2+]i, as well as prevented a subsequent, additive elevation in [Ca2+]i by Delta9-THC, independent of protein kinase C. Reverse transcriptase-polymerase chain reaction analysis for TRPC1-7 showed that HPB-ALL cells express detectable mRNA levels of only TRPC1. Finally, small interference RNA knockdown of TRPC1 attenuated the Delta9-THC-mediated elevation of [Ca2+]i. Collectively, these results suggest that Delta9-THC-induced elevation in [Ca2+]i is attributable entirely to extracellular calcium influx, which is independent of [Ca2+]i store depletion, and is mediated, at least partially, through the DAG-sensitive TRPC1 channels.

Analgesics, Non-Narcotic↗
PubMed2006

Old molecules for new receptors: Trp(Nps) dipeptide derivatives as vanilloid TRPV1 channel blockers.

The transient receptor potential vanilloid member 1 (TRPV1), an integrator of multiple pain-producing stimuli, is regarded nowadays as an important biological target for the discovery of novel analgesics. Here, we describe the first experimental evidence for the behavior of an old family of analgesic dipeptides, namely Xaa-Trp(Nps) and Trp(Nps)-Xaa (Xaa=Lys, Arg) derivatives, as potent TRPV1 channel blockers. We also report the synthesis and biological investigation of a series of new conformationally restricted Trp(Nps)-dipeptide derivatives with improved TRPV1/NMDA selectivity. Compound 15 b, which incorporates an N-terminal 2S-azetidine-derived Arg residue, was the most selective compound in this series. Collectively, a new family of TRPV1 channel blockers emerged from our results, although further modifications are required to fine-tune the potency/selectivity/toxicity balance.

Animals↗
PubMed2006

Upregulation of TRPC1 in the development of cardiac hypertrophy.

The importance of Ca(2+) entry in the cardiac hypertrophic response is well documented, but the actual Ca(2+) entry channels remain unknown. Transient receptor potential (TRP) proteins are thought to form either homo- or heteromeric Ca(2+) entry channels that are involved in the proliferation and differentiation of various cells. The purpose of this study was to explore the potential involvement of TRP channels in the development of cardiac hypertrophy. The mRNA and protein expression of several TRP channel subunits were evaluated using hearts from abdominal aortic-banded (AAB) rats. Although TRPs C1, C3, C5, and C6 were constitutively expressed, only TRPC1 expression was significantly increased in the hearts of AAB rats compared to sham-operated rats. Using primary cultures of neonatal rat cardiomyocytes, we detected increases in the expression of TRPC1, brain natriuretic peptide (BNP), and atrial natriuretic factor (ANF), as well as increases in store-operated Ca(2+) entry (SOCE) and cell surface area, following endothelin-1 (ET-1) treatment. Silencing of the TRPC1 gene via small interfering RNA (siRNA) attenuated SOCE and prevented ET-1-, angiotensin-II (AT II)-, and phenylephrine (PE)-induced cardiac hypertrophy. In HEK 293T cells, overexpression of TRPC1 augmented SOCE, leading to an increase in nuclear factor of activated T cells (NFAT) promoter activity, while co-transfection with dominant-negative forms of TRPC1 suppressed it. In conclusion, TRPC1 functions in Ca(2+) influx, and its upregulation is involved in the development of cardiac hypertrophy; moreover, it plays an important role in the regulation of the signaling pathways that govern cardiac hypertrophy. These findings establish TRPC1 as a functionally important regulator of cardiac hypertrophy.

Animals↗
PubMed2005

Generation of functional ion-channel tools by E3 targeting.

Here we describe a strategy for generating ion-channel inhibitors. It takes advantage of antibody specificity combined with a pattern recognition approach that targets the third extracellular region (E3) of a channel. To test the concept, we first focused on TRPC5, a member of the transient receptor potential (TRP) calcium channel family, the study of which has been hindered by poor pharmacological tools. Extracellular application of E3-targeted anti-TRPC5 antibody led to a specific TRPC5 inhibitor, enabling TRPC5 to be distinguished from its closest family members, and TRPC5 function to be explored in a relatively intractable physiological system. E3 targeting was further applied to voltage-gated sodium channels, leading to discovery of a subtype-specific inhibitor of Na(V)1.5. These examples illustrate the potential power of E3 targeting as a systematic method for producing gene-type specific ion-channel inhibitors for use in routine assays on cells or tissues from a range of species and having therapeutic potential.

Antibodies, Monoclonal↗
PubMed2004

Diversity of TRP channel activation.

Calcium entry controls a plethora of short- and long-term cell functions. With respect to the activation mechanisms of Ca2+ entry channels they are subdivided in the thoroughly characterized voltage-gated Ca2+ channels and the non-voltage gated Ca2+ channels. The latter group includes cation channels of the 'transient receptor potential' (TRP) superfamily, which consists of three subfamilies (TRPC, TRPV, TRPM). Activation of TRP channels is not yet completely understood, but examples of activation mechanisms of TRP channels from all three subfamilies will be discussed. The main focus is on the members of the TRPV subfamily, among which the TRPV4 channel shows a surprising gating promiscuity. It can be activated by cell swelling, heat and phorbol esters. Endogenous activators of the channel have not yet been described. It will be shown that lipid messengers related to arachidonic acid are endogenous TRPV4 activators. For TRPV5 and 6, the only highly Ca2+ selective channels within the TRP super-family, a voltage-dependent gating mechanism will be discussed, which includes an open pore block by Mg2+ and a highly Ca2+-sensitive mechanism of inactivation. Regulation of channel availability by interaction with a protein bound to a site at the C-terminus of both channels will be demonstrated. Functional consequences of these different mechanisms of gating will be discussed.

Animals↗
PubMed2000

Metabolic stress reversibly activates the Drosophila light-sensitive channels TRP and TRPL in vivo.

Drosophila transient receptor potential (TRP) is a prototypical member of a novel family of channel proteins underlying phosphoinositide-mediated Ca(2+) entry. Although the initial stages of this signaling cascade are well known, downstream events leading to the opening of the TRP channels are still obscure. In the present study we applied patch-clamp whole-cell recordings and measurements of Ca(2+) concentration by ion-selective microelectrodes in eyes of normal and mutant Drosophila to isolate the TRP and TRP-like (TRPL)-dependent currents. We report that anoxia rapidly and reversibly depolarizes the photoreceptors and induces Ca(2+) influx into these cells in the dark. We further show that openings of the light-sensitive channels, which mediate these effects, can be obtained by mitochondrial uncouplers or by depletion of ATP in photoreceptor cells, whereas the effects of illumination and all forms of metabolic stress were additive. Effects similar to those found in wild-type flies were also found in mutants with strong defects in rhodopsin, Gq-protein, or phospholipase C, thus indicating that the metabolic stress operates at a late stage of the phototransduction cascade. Genetic elimination of both TRP and TRPL channels prevented the effects of anoxia, mitochondrial uncouplers, and depletion of ATP, thus demonstrating that the TRP and TRPL channels are specific targets of metabolic stress. These results shed new light on the properties of the TRP and TRPL channels by showing that a constitutive ATP-dependent process is required to keep these channels closed in the dark, a requirement that would make them sensitive to metabolic stress.

2,4-Dinitrophenol↗