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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↗
PubMed2004

Genetic models of mechanotransduction: the nematode Caenorhabditis elegans.

Mechanotransduction, the conversion of a mechanical stimulus into a biological response, constitutes the basis for a plethora of fundamental biological processes such as the senses of touch, balance, and hearing and contributes critically to development and homeostasis in all organisms. Despite this profound importance in biology, we know remarkably little about how mechanical input forces delivered to a cell are interpreted to an extensive repertoire of output physiological responses. Recent, elegant genetic and electrophysiological studies have shown that specialized macromolecular complexes, encompassing mechanically gated ion channels, play a central role in the transformation of mechanical forces into a cellular signal, which takes place in mechanosensory organs of diverse organisms. These complexes are highly efficient sensors, closely entangled with their surrounding environment. Such association appears essential for proper channel gating and provides proximity of the mechanosensory apparatus to the source of triggering mechanical energy. Genetic and molecular evidence collected in model organisms such as the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the mouse highlight two distinct classes of mechanically gated ion channels: the degenerin (DEG)/epithelial Na(+) channel (ENaC) family and the transient receptor potential (TRP) family of ion channels. In addition to the core channel proteins, several other potentially interacting molecules have in some cases been identified, which are likely parts of the mechanotransducing apparatus. Based on cumulative data, a model of the sensory mechanotransducer has emerged that encompasses our current understanding of the process and fulfills the structural requirements dictated by its dedicated function. It remains to be seen how general this model is and whether it will withstand the impiteous test of time.

Animals↗
PubMed2005

TRPV channels as thermosensory receptors in epithelial cells.

Temperature-sensitive transient receptor potential vanilloid (TRPV) ion channels are critical contributors to normal pain and temperature sensation and therefore represent attractive targets for pain therapy. When these channels were first discovered, most attention was focused on their potential contributions to direct thermal activation of peripheral sensory neurons. However, recent anatomical, physiological, and behavioral studies have provided evidence that TRPV channels expressed in skin epithelial cells may also contribute to thermosensation in vitro and in vivo. Here, we review these studies and speculate on possible communication mechanisms from cutaneous epithelial cells to sensory neurons.

Animals↗
PubMed2006

Ca2+ signaling, TRP channels, and endothelial permeability.

Increased endothelial permeability is the hallmark of inflammatory vascular edema. Inflammatory mediators that bind to heptahelical G protein-coupled receptors trigger increased endothelial permeability by increasing the intracellular Ca2+ concentration ([Ca2+]i). The rise in [Ca2+]i activates key signaling pathways that mediate cytoskeletal reorganization (through myosin-light-chain-dependent contraction) and the disassembly of VE-cadherin at the adherens junctions. The Ca2+-dependent protein kinase C (PKC) isoform PKCalpha plays a crucial role in initiating endothelial cell contraction and disassembly of VE-cadherin junctions. The increase in [Ca2+]i induced by inflammatory agonists such as thrombin and histamine is achieved by the generation of inositol 1,4,5-trisphosphate (IP3), activation of IP3-receptors, release of stored intracellular Ca2+, and Ca2+ entry through plasma membrane channels. IP3-sensitive Ca2+-store depletion activates plasma membrane cation channels (i.e., store-operated cation channels [SOCs] or Ca2+ release-activated channels [CRACs]) to cause Ca2+ influx into endothelial cells. Recent studies have identified members of Drosophila transient receptor potential (TRP) gene family of channels that encode functional SOCs in endothelial cells. These studies also suggest that the canonical TRPC homologue TRPC1 is the predominant isoform expressed in human vascular endothelial cells, and is the essential component of the SOC in this cell type. Further, evidence suggests that the inflammatory cytokine tumor necrosis factor-alpha can induce the expression of TRPC1 in human vascular endothelial cells signaling via the nuclear factor-kappaB pathway. Increased expression of TRPC1 augments Ca2+ influx via SOCs and potentiates the thrombin-induced increase in permeability in human vascular endothelial cells. Deletion of the canonical TRPC homologue in mouse, TRPC4, caused impairment in store-operated Ca2+ current and Ca2+-store release-activated Ca2+ influx in aortic and lung endothelial cells. In TRPC4 knockout (TRPC4-/-) mice, acetylcholine-induced endothelium-dependent smooth muscle relaxation was drastically reduced. In addition, TRPC4-/- mouse-lung endothelial cells exhibited lack of actin-stress fiber formation and cell retraction in response to thrombin activation of protease-activated receptor-1 (PAR-1) in endothelial cells. The increase in lung microvascular permeability in response to PAR-1 activation was inhibited in TRPC4-/- mice. These results indicate that endothelial TRP channels such as TRPC1 and TRPC4 play an important role in signaling agonist-induced increases in endothelial permeability.

Animals↗
PubMed2003

Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels.

TRPV4 is a widely expressed cation channel of the 'transient receptor potential' (TRP) family that is related to the vanilloid receptor VR1 (TRPV1). It functions as a Ca2+ entry channel and displays remarkable gating promiscuity by responding to both physical stimuli (cell swelling, innoxious heat) and the synthetic ligand 4alphaPDD. An endogenous ligand for this channel has not yet been identified. Here we show that the endocannabinoid anandamide and its metabolite arachidonic acid activate TRPV4 in an indirect way involving the cytochrome P450 epoxygenase-dependent formation of epoxyeicosatrienoic acids. Application of 5',6'-epoxyeicosatrienoic acid at submicromolar concentrations activates TRPV4 in a membrane-delimited manner and causes Ca2+ influx through TRPV4-like channels in vascular endothelial cells. Activation of TRPV4 in vascular endothelial cells might therefore contribute to the relaxant effects of endocannabinoids and their P450 epoxygenase-dependent metabolites on vascular tone.

8,11,14-Eicosatrienoic Acid↗
PubMed2002

Calcium oscillation linked to pacemaking of interstitial cells of Cajal: requirement of calcium influx and localization of TRP4 in caveolae.

Interstitial cells of Cajal (ICC) are considered to be pacemaker cells in gastrointestinal tracts. ICC generate electrical rhythmicity (dihydropyridine-insensitive) as slow waves and drive spontaneous contraction of smooth muscles. Although cytosolic Ca(2+) has been assumed to play a key role in pacemaking, Ca(2+) movements in ICC have not yet been examined in detail. In the present study, using cultured cell clusters isolated from mouse small intestine, we demonstrated Ca(2+) oscillations in ICC. Fluo-4 was loaded to the cell cluster, the relative amount of cytosolic Ca(2+) was recorded, and ICC were identified by c-Kit immunoreactivity. We specifically detected Ca(2+) oscillation in ICC in the presence of dihydropyridine, which abolishes Ca(2+) oscillation in smooth muscles. The oscillation was coupled to the electrical activity corresponding to slow waves, and it depended on Ca(2+) influx through a non-selective cation channel, which was SK&F 96365-sensitive and store-operated. We further demonstrated the presence of transient receptor potential-like channel 4 (TRP4) in caveolae of ICC. Taken together, the results infer that the Ca(2+) oscillation in ICC is intimately linked to the pacemaker function and depends on Ca(2+) influx mediated by TRP4.

Animals↗
PubMed2004

Activation of the Drosophila TRP and TRPL channels requires both Ca2+ and protein dephosphorylation.

The Transient Receptor Potential (TRP) proteins constitute a large and diverse family of channel proteins, which is conserved through evolution. TRP channel proteins have critical functions in many tissues and cell types, but their gating mechanism is an enigma. In the present study patch-clamp whole-cell recordings was applied to measure the TRP- and TRP-like (TRPL)-dependent currents in isolated Drosophila ommatidia. Also, voltage responses to light and to metabolic stress were recorded from the eye in vivo. We report new insight into the gating of the Drosophila light-sensitive TRP and TRPL channels, by which both Ca2+ and protein dephosphorylation are required for channel activation. ATP depletion or inhibition of protein kinase C activated the TRP channels, while photo-release of caged ATP or application of phorbol ester antagonized channels openings in the dark. Furthermore, Mg(2+)-dependent stable phosphorylation event by ATPgammaS or protein phosphatase inhibition by calyculin A abolished activation of the TRP and TRPL channels. While a high reduction of cellular Ca2+ abolished channel activation, subsequent application of Ca2+ combined with ATP depletion induced a robust dark current that was reminiscent of light responses. The results suggest that the combined action of Ca2+ and protein dephosphorylation activate the TRP and TRPL channels, while protein phosphorylation by PKC antagonized channels openings.

Animals↗
PubMed2001

[Molecular candidates for capacitative calcium entry channel].

The emptying of intracellular calcium store generates a putative signal that induces the opening of the store-operated calcium channel (SOC) at the level of the cell membrane, also known as the capacitative calcium entry (CCE), or the calcium release-activated calcium channel (CRAC), which allows entry of calcium into the cells from the extracellular space. Drosophila transient receptor potential (trp) and trp-like(trpl) genes have been identified and reported to code cation channels(TRP and TRPL). The mechanism of coupling between store depletion and channel opening is unknown. Three fundamental mechanisms have been proposed for transmitting the signal from intracellular stores to the plasma membrane: (1) a diffusible message; (2) protein-protein interactions; and (3) vesicle secretion. This review focuses primarily on the recent studies on the TRP homologues, the possible mechanisms and electrophysiological phenotypes of capacitative calcium entry.

Animals↗
PubMed2003

Mechanisms involved in the increase in intracellular calcium following hypotonic shock in bovine articular chondrocytes.

The extracellular osmotic environment of chondrocytes fluctuates during joint loading as fluid is expressed from and reimbibed by the extracellular matrix. Matrix synthesis by chondrocytes is modulated by joint loading, possibly mediated by variations in intracellular composition. The present study has employed the Ca2+-sensitive fluoroprobe Fura-2 to determine the effects of hypotonic shock (HTS) on intracellular Ca2+ concentration ([Ca2+]i) and to characterise the mechanisms involved in the response for isolated bovine articular chondrocytes. In cells subjected to a 50% dilution, [Ca2+]i rapidly increased by approximately 250%, a sustained plateau being achieved within 300 s. The effect was inhibited by thapsigargin or by removal of extracellular Ca2+, indicating that the rise in [Ca2+]i reflects both influx from the extracellular medium and release from intracellular stores. Inhibition of the response by neomycin implicates activation of PLC and IP3 synthesis in the mobilisation of Ca2+ from intracellular stores. The rise was insensitive to inhibitors of L-type voltage-activated Ca2+ channels (LVACC) or reverse mode Na+/Ca2+ exchange (NCE) but could be significantly attenuated by ruthenium red, an inhibitor of transient receptor potential vanilloid (TRPV) channels and by Gd3+, a blocker of stretch-activated cation (SAC) channels. The HTS-induced rise in [Ca2+]i was almost completely absent in cells treated with Ni2+, a non-specific inhibitor of Ca2+ entry pathways. We conclude that in response to HTS the opening of SACC and a member of TRPV channel family leads to Ca2+ influx, simultaneously with the release from intracellular stores.

Adaptation, Physiological↗
PubMed2000

Inhibition of TRP3 channels by lanthanides. Block from the cytosolic side of the plasma membrane.

The lanthanide ions La(3+) and Gd(3+) block Ca(2+)-permeable cation channels and have been used as important tools to characterize channels of the transient receptor potential (TRP) family. However, widely different concentrations of La(3+) and Gd(3+) have reportedly been required for block of TRP3 channels in various expression systems. The present study provides a possible explanation for this discrepancy. After overexpression of TRP3 in Chinese hamster ovary cells, whole-cell currents through TRP3 were reversibly inhibited by La(3+) with an EC(50) of 4 microm. For comparison, the organic blocker SKF96365 required an EC(50) of 8 microm. Gd(3+) blocked with an EC(50) of 0.1 microm, but this block was slow in onset and was not reversible after wash-out. When the two lanthanides were added to the cytosolic side of inside-out patches, block was achieved with considerably lower concentrations (EC(50) for La(3+), 0.02 microm; EC(50) for Gd(3+), 0.02 microm). Uptake of La(3+) into the cytosol of Chinese hamster ovary cells was demonstrated with intracellular fura-2. We conclude that lanthanides block TRP3 more potently from the cytosolic than from the extracellular side of the plasma membrane and that uptake of lanthanides will largely affect the apparent EC(50) values after extracellular application.

Animals↗
PubMed2004

The TRPM ion channel subfamily: molecular, biophysical and functional features.

Significant progress in the molecular and functional characterization of a subfamily of genes that encode melastatin-related transient receptor potential (TRPM) cation channels has been made during the past few years. This subgroup of the TRP superfamily of ion channels contains eight mammalian members and has isoforms in most eukaryotic organisms. The individual members of the TRPM subfamily have specific expression patterns and ion selectivity, and their specific gating and regulatory mechanisms are tailored to integrate multiple signaling pathways. The diverse functional properties of these channels have a profound effect on the regulation of ion homoeostasis by mediating direct influx of Ca2+, controlling Mg2+ entry, and determining the potential of the cell membrane. TRPM channels are involved in several physiological and pathological conditions in electrically excitable and non-excitable cells, which make them exciting targets for drug discovery.

Animals↗
PubMed2003

Localisation of cannabinoid receptor 1 in rat dorsal root ganglion using in situ hybridisation and immunohistochemistry.

In this study we used in situ hybridisation and double-labelling immunohistochemistry to characterise cannabinoid receptor 1 (CB(1)) expression in rat lumbar dorsal root ganglion (DRG) neurons.Approximately 25% of DRG neurons expressed CB(1) mRNA and displayed immunoreactivity for CB(1). Sixty-nine percent to 82% of CB(1)-expressing cells were also immunoreactive for neurofilament 200, indicative of myelinated A-fibre neurons, which tend to be large- and medium-sized DRG neurons (>600 microm(2)). Approximately 10% of CB1-expressing cells also expressed transient receptor potential vanilloid family ion channel 2 (TRPV2), the noxious heat-transducing channel found in medium to large lightly myelinated Adelta-fibre DRG neurons. Seventeen percent to 26% of CB(1)-expressing cells co-stained using Isolectin B4, 9-10% for calcitonin gene-related peptide and 11-20% for transient receptor potential vanilloid family ion channel 1 (TRPV1), predominantly markers of small non-myelinated C-fibre DRG neurons (<600 microm(2)). These findings suggest that whilst a wide range of DRG neuron phenotypes express CB(1), it is predominantly associated with myelinated fibres.

Animals↗
PubMed2006

The TRPM7 ion channel functions in cholinergic synaptic vesicles and affects transmitter release.

A longstanding hypothesis is that ion channels are present in the membranes of synaptic vesicles and might affect neurotransmitter release. Here we demonstrate that TRPM7, a member of the transient receptor potential (TRP) ion channel family, resides in the membrane of synaptic vesicles of sympathetic neurons, forms molecular complexes with the synaptic vesicle proteins synapsin I and synaptotagmin I, and directly interacts with synaptic vesicular snapin. In sympathetic neurons, changes in TRPM7 levels and channel activity alter acetylcholine release, as measured by EPSP amplitudes and decay times in postsynaptic neurons. TRPM7 affects EPSP quantal size, an intrinsic property of synaptic vesicle release. Targeted peptide interference of TRPM7's interaction with snapin affects the amplitudes and kinetics of postsynaptic EPSPs. Thus, vesicular TRPM7 channel activity is critical to neurotransmitter release in sympathetic neurons.

Acetylcholine↗
PubMed2006

TRP proteins and cancer.

Cancer is the second most common cause of death in western countries. It is therefore of fundamental importance to improve the treatment of patients with malignant tumors. This goal can only be achieved if we get closer insight in the various mechanisms leading to tumor formation. Significant progress in the understanding of carcinogenesis has been made during the last couple of years. Ion channels contribute to the regulation of cell proliferation which has initially been shown for K+ channels. Meanwhile, other ion channels such as Cl-, Na+ and Ca2+ channels seem to influence cellular function like growth, migration and invasion. In addition, cation channels of the transient receptor potential (TRP) superfamily are implicated in cancer formation. 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. Furthermore, TRP channel structure and function will be discussed in the light of their possible importance as prognostic markers and targets for drug discovery.

Calcium Channels↗
PubMed2006

Receptor-independent actions of cannabinoids on cell membranes: focus on endocannabinoids.

Cannabinoids are a structurally diverse group of mostly lipophilic molecules that bind to cannabinoid receptors. In fact, endogenous cannabinoids (endocannabinoids) are a class of signaling lipids consisting of amides and esters of long-chain polyunsaturated fatty acids. They are synthesized from lipid precursors in plasma membranes via Ca(2+) or G-protein-dependent processes and exhibit cannabinoid-like actions by binding to cannabinoid receptors. However, endocannabinoids can produce effects that are not mediated by these receptors. In pharmacologically relevant concentrations, endocannabinoids modulate the functional properties of voltage-gated ion channels including Ca(2+) channels, Na(+) channels, various types of K(+) channels, and ligand-gated ion channels such as serotonin type 3, nicotinic acetylcholine, and glycine receptors. In addition, modulatory effects of endocannabinoids on other ion-transporting membrane proteins such as transient potential receptor-class channels, gap junctions and transporters for neurotransmitters have also been demonstrated. Furthermore, functional properties of G-protein-coupled receptors for different types of neurotransmitters and neuropeptides are altered by direct actions of endocannabinoids. Although the mechanisms of these effects are currently not clear, it is likely that these direct actions of endocannabinoids are due to their lipophilic structures. These findings indicate that additional molecular targets for endocannabinoids exist and that these targets may represent novel sites for cannabinoids to alter either the excitability of the neurons or the response of the neuronal systems. This review focuses on the results of recent studies indicating that beyond their receptor-mediated effects, endocannabinoids alter the functions of ion channels and other integral membrane proteins directly.

Animals↗
PubMed2005

Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect.

1 2-aminoethoxydiphenyl borate (2-APB) has been widely used to examine the roles of inositol 1,4,5-trisphosphate receptors (IP3Rs) and store-operated Ca2+ entry and is an emerging modulator of cationic channels encoded by transient receptor potential (TRP) genes. 2 Using Ca2+-indicator dye and patch-clamp recording we first examined the blocking effect of 2-APB on human TRPC5 channels expressed in HEK-293 cells. 3 The concentration-response curve has an IC50 of 20 microM and slope close to 1.0, suggesting one 2-APB molecule binds per channel. The blocking effect is not shared by other Ca2+ channel blockers including methoxyverapamil, nifedipine, N-propargylnitrendipine, or berberine. 4 In whole-cell and excised membrane patch recordings, 2-APB acts from the extracellular but not intracellular face of the membrane. 5 Block of TRPC5 by 2-APB is less at positive voltages, suggesting that it enters the electric field or acts by modulating channel gating. 6 2-APB also blocks TRPC6 and TRPM3 expressed in HEK-293 cells, but not TRPM2. 7 Block of TRP channels by 2-APB may be relevant to cell proliferation because 2-APB has a greater inhibitory effect on proliferation in cells overexpressing TRPC5. 8 Our data indicate a specific and functionally important binding site on TRPC5 that enables block by 2-APB. The site is only available via an extracellular route and the block shows mild voltage-dependence.

Animals↗
PubMed2006

Receptor-independent effects of endocannabinoids on ion channels.

Endogenous cannabinoids (endocannabinoids), produced from membrane-bound precursors via calcium and/or G-protein dependent processes, mimic the effects of cannabinoids by activating cannabinoid CB(1) and/or CB(2) receptors. Several reports however, also indicate that endocannabinoids can produce effects that are independent of cannabinoid receptors. Thus, in pharmacologically relevant concentrations, endocannabinoids have been demonstrated to modulate the functional properties of voltage-gated ion channels including Ca(2+) channels, Na(+) channels and various types of K(+) channels, and ligand-gated ion channels such as 5-HT(3), and nicotinic ACh receptors. In addition, the functional modulations by endocannabinoids of other ion-transporting membrane proteins such as transient potential receptor-class channels, gap junctions, and neurotransmitter transporters have also been reported. These findings indicate that additional molecular targets for endocannabinoids exist and that these targets may represent important sites for cannabinoids to alter either the excitability of the neurons or the response of the neuronal systems. This review focuses on the results of recent studies indicating that beyond their receptor-mediated effects, endocannabinoids alter the function of ion channels directly.

Animals↗