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The canonical transient receptor potential (TRPC) cation channels are mammalian homologs of the photoreceptor channel TRP in Drosophila melanogaster. All seven TRPCs (TRPC1 through TRPC7) can be activated through Gq/11 receptors or receptor tyrosine kinase (RTK) by mechanisms downstream of phospholipase C. The last decade saw a rapidly growing interest in understanding the role of TRPC channels in calcium entry pathways as well as in understanding the signal(s) responsible for TRPC activation. TRPC channels have been proposed to be activated by a variety of signals including store depletion, membrane lipids, and vesicular insertion into the plasma membrane. Here we discuss recent developments in the mode of activation as well as the pharmacological and electrophysiological properties of this important and ubiquitous family of cation channels. [ABSTRACT FROM AUTHOR]

TRP channels, in particular the TRPC and TRPV subfamilies, have emerged as important constituents of the receptor-activated Ca2+ influx mechanism triggered by hormones, growth factors, and neurotransmitters through activation of phospholipase C (PLC). Several TRPC channels are also activated by passive depletion of endoplasmic reticulum (ER) Ca2+. Although in several studies the native TRP channels faithfully reproduce the respective recombinant channels, more often the properties of Ca2+ entry and/or the store-operated current are strikingly different from that of the TRP channels expressed in the same cells. The present review aims to discuss this disparity in the context of interaction of TRPC channels with auxiliary proteins that may alter the permeation and regulation of TRPC channels. [ABSTRACT FROM AUTHOR]

TRPC channels are ubiquitously expressed among cell types and mediate signals in response to phospholipase C (PLC)-coupled receptors. TRPC channels function as integrators of multiple signals resulting from receptor-induced PLC activation, which catalyzes the breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 depletes Ca2+ stores and TRPC3 channels can be activated by store-depletion. InsP3 also activates the InsP3 receptor, which may undergo direct interactions with the TRPC3 channel, perhaps mediating store-dependence. The other PLC product, DAG, has a direct non-PKC-dependent activating role on TRPC3 channels likely by direct binding. DAG also has profound effects on the TRPC3 channel through PKC. Thus PKC is a powerful inhibitor of most TRPC channels and DAG is a dual regulator of the TRPC3 channel. PLC-mediated DAG results in rapid channel opening followed later by a slower DAG-induced PKC-mediated deactivation of the channel. The decreased level of PIP2 from PLC activation also has an important modifying action on TRPC3 channels. Thus, the TRPC3 channel and PLCγ form an intermolecular PH domain that has high specificity for binding PIP2. This interaction allows the channel to be retained within the plasma membrane, a further operational control factor for TRPC3. As nonselective cation channels, TRPC channel opening results in the entry of both Na+ and Ca2+ ions. Thus, while they may mediate Ca2+ entry signals, TRPC channels are also powerful modifiers of membrane potential. [ABSTRACT FROM AUTHOR]

Transient receptor potential (TRP) channels are members of a relatively newly described family of cation channels that display a wide range of properties and mechanisms of activation. The exact physiological function and regulation of most of these channels have not yet been conclusively determined. Studies over the past decade have revealed important features of the channels that contribute to their function. These include homomeric interactions between TRP monomers, selective heteromeric interactions within members of the same subfamily, interactions of TRPs with accessory proteins and assembly into macromolecular signaling complexes, and regulation within functionally distinct cellular microdomains. Further, distinct constitutive and regulated vesicular trafficking mechanisms have a critical role not only in controlling the surface expression of TRP channels but also their activation in response to stimuli. A number of cellular components such as cytoskeletal and scaffolding proteins also contribute to TRP channel trafficking. Thus, mechanisms involved in the assembly and trafficking of TRP channels control their plasma membrane expression and critically impact their function and regulation. [ABSTRACT FROM AUTHOR]

Ca2+, nitric oxide (NO), and protein kinase G (PKG) are important signaling molecules that play pivotal roles in many physiological processes such as vascular tone control, platelet activation, and synaptic plasticity. TRPC channels allow Ca2+ influx, thus contributing to the production of NO, which subsequently stimulates PKG. It has been demonstrated that PKG can phosphorylate human TRPC3 at Thr-11 and Ser-263 and that this phosphorylation inactivates TRPC3. These two PKG phosphorylation sites, Thr-11 and Ser-263 in human TRPC3, are conserved in other members of the TRPC3/6/7 subfamily, suggesting that PKG may also phosphorylate TRPC6 and TRPC7. In addition, protein kinase C (PKC) also inactivates TRPC3, partly through activating PKG. The PKG-mediated inhibition of TRPC channels may provide a feedback control for the fine tuning of [Ca2+]i levels and protect the cells from the detrimental effects of excessive [Ca2+]i and/or NO. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol-4,5-bisphosphate (PIP2) has emerged as a versatile regulator of TRP ion channels. In many cases, the regulation involves interactions of channel proteins with the lipid itself independent of its hydrolysis products. The functions of the regulation mediated by such interactions are diverse. Some TRP channels absolutely require PIP2 for functioning, while others are inhibited. A change of gating is common to all, endowing the lipid a role for modulation of the sensitivity of the channels to their physiological stimuli. The activation of TRP channels may also influence cellular PIP2 levels via the influx of Ca2+ through these channels. Depletion of PIP2 in the plasma membrane occurs upon activation of TRPV1, TRPM8, and possibly TRPM4/5 in heterologous expression systems, whereas resynthesis of PIP2 requires Ca2+ entry through the TRP/TRPL channels in Drosophila photoreceptors. These developments concerning PIP2 regulation of TRP channels reinforce the significance of the PLC signaling cascade in TRP channel function, and provide further perspectives for understanding the physiological roles of these ubiquitous and often enigmatic channels. [ABSTRACT FROM AUTHOR]

Pain is initiated when noxious stimuli excite the peripheral terminals of specialized primary afferent neurons called nociceptors. Many molecules are involved in conversion of the noxious stimuli to the electrical signals in the nociceptor endings. Among them, TRP channels play important roles in detecting noxious stimuli. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mast cells are tissue-resident immune effector cells. They respond to diverse stimuli by releasing potent biological mediators into the surrounding tissue, and initiating inflammatory responses that promote wound healing and infection clearance. In addition to stimulation via immunological routes, mast cells also respond to polybasic secretagogues and physical stimuli. Each mechanism for mast cell activation relies on the influx of calcium through specific ion channels in the plasma membrane. Recent reports suggest that several calcium-permeant cation channels of the TRPV family are expressed in mast cells. TRPV channels are a family of sensors that receive and react to chemical messengers and physical environmental cues, including thermal, osmotic, and mechanical stimuli. The central premise of this review is that TRPVs transduce physiological and pathophysiological cues that are functionally coupled to calcium signaling and mediator release in mast cells. Inappropriate mast cell activation is at the core of numerous inflammatory pathologies, rendering the mast cell TRPV channels potentially important therapeutic targets. [ABSTRACT FROM AUTHOR]

TRP proteins form ion channels that are activated following receptor stimulation. Several members of the TRP family are likely to be expressed in lymphocytes. However, in many studies, messenger RNA (mRNA) but not protein expression was analyzed and cell lines but not primary human or murine lymphocytes were used. Among the expressed TRP mRNAs are TRPC1, TRPC3, TRPM2, TRPM4, TRPM7, TRPV1, and TRPV2. Regulation of Ca2+ entry is a key process for lymphocyte activation, and TRP channels may both increase Ca2+ influx (such as TRPC3) or decrease Ca2+ influx through membrane depolarization (such as TRPM4). In the future, linking endogenous Ca2+/cation channels in lymphocytes with TRP proteins should lead to a better molecular understanding of lymphocyte activation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Orchestrated ion fluctuations within pancreatic islets regulate hormone secretion and may be essential to processes such as apoptosis. A diverse set of ion channels allows for islet cells to respond to a variety of signals and dynamically regulate hormone secretion and glucose homeostasis (reviewed by Houamed et al. 2004). This chapter focuses on transient receptor potential (TRP)-related channels found within the beta cells of the islet and reviews their roles in both insulin secretion and apoptosis. [ABSTRACT FROM AUTHOR]

On the basis of their ever-expanding roles, not only in sensory signaling but also in a plethora of other, often Ca2+-mediated actions in cell and whole body homeostasis, it is suggested that mutations in TRP channel genes not only cause disease states but also contribute in more subtle ways to simple and complex diseases. A survey is therefore presented of diseases and syndromes that map to one or multiple chromosomal loci containing TRP channel genes. A visual map of the chromosomal locations of TRP channel genes in man and mouse is also presented. [ABSTRACT FROM AUTHOR]

Polycystin-2, or TRPP2 according to the TRP nomenclature, is encoded by PKD2, a gene mutated in patients with autosomal-dominant polycystic kidney disease. Its precise subcellular location and its intracellular trafficking are a matter of intense debate, although a consensus has emerged that it is located in primary cilia, a long-neglected organelle possibly involved in sensory functions. Polycystin-2 has a calculated molecular mass of 110 kDa, and according to structural predictions it contains six membrane-spanning domains and a pore-forming region between the 5th and 6th membrane-spanning domain. This section first introduces the reader to the field of cystic kidney diseases and to the PKD2 gene, before the ion channel properties of polycystin-2 are discussed in great detail. [ABSTRACT FROM AUTHOR]

The TRPA1 protein has up to 18 N-terminal and presumed cytoplasmic ankyrin repeats followed by the six membrane spanning and single pore-loop domains characteristic of all TRPs. In mice, TRPA1 is almost exclusively expressed in nociceptive neurons of peripheral ganglia and in all the mechanosensory epithelia of inner ear. In nociceptive neurons, TRPA1 mediates the response to the proalgesic bradykinin as well as the response to pungent irritants found in mustards and garlic, and probably also to those found in cinnamon and tear gas. The channel properties of TRPA1 are discussed and compared to those of sensory transducers. TRPA1 is well conserved across the animal kingdom, with likely orthologs from human to nematode, which suggest an ancestral role for this channel, probably in sensation. [ABSTRACT FROM AUTHOR]

Originally cloned as a prostate-specific protein, TRPM8 is now best known as a cold- and menthol-activated channel implicated in thermosensation. In this chapter we provide a brief review of current knowledge concerning the biophysical properties, gating mechanisms, pharmacology and (patho)physiology of this TRP channel. [ABSTRACT FROM AUTHOR]

TRPM7 is a member of the melastatin-related subfamily of TRP channels and represents a protein that contains both an ion channel and a kinase domain. The protein is ubiquitously expressed and represents the only ion channel known that is essential for cellular viability. TRPM7 is a divalent cation-selective ion channel that is permeable to Ca2+ and Mg2+, but also conducts essential metals such as Zn2+, Mn2+, and Co2+, as well as nonphysiologic or toxic metals such as Ni2+, Cd2+, Ba2+, and Sr2+. The channel is constitutively open but strongly downregulated by intracellular levels of Mg2+ and MgATP and other Mg-nucleotides. Reducing the cellular levels of these regulators leads to activation of TRPM7-mediated currents that exhibit a characteristic nonlinear current-voltage relationship with pronounced outward rectification due to divalent influx at physiologically negative voltages and monovalent outward fluxes at positive voltages. TRPM7 channel activity is also actively regulated following receptor-mediated changes in cyclic AMP (cAMP) and protein kinase A activity. This regulation as well as that by Mg-nucleotides requires a functional endogenous kinase domain. The function of the kinase domain is not completely understood, but may involve autophosphorylation of TRPM7 as well as phosphorylation of other target proteins such as annexin and myosin IIA heavy chain. Based on these properties, TRPM7 is currently believed to represent a ubiquitous homeostatic mechanism that regulates Ca2+ and Mg2+ fluxes based on the metabolic state of the cell. Physiologically, the channel may serve as a regulated transport mechanism for these ions that could affect cell adhesion, cell growth and proliferation, and even cell death under pathological stress such as anoxia. [ABSTRACT FROM AUTHOR]

TRPM5 is a cation channel that it is essential for transduction of bitter, sweet and umami tastes. Signaling of these tastes involves the activation of G protein-coupled receptors that stimulate phospholipase C (PLC) β2, leading to the breakdown of phosphatidylinositol bisphosphate (PIP2) into diacylglycerol (DAG) and inositol trisphosphate (IP3), and release of Ca2+ from intracellular stores. TRPM5 forms a nonselective cation channel that is directly activated by Ca2+ and it is likely to be the downstream target of this signaling cascade. Therefore, study of TRPM5 promises to provide insight into fundamental mechanisms of taste transduction. This review highlights recent work on the mechanisms of activation of the TRPM5 channel. Themouse TRPM5 gene encodes a protein of 1,158 amino acids that is proposed to have six transmembrane domains and to function as a tetramer. TRPM5 is structurally most closely related to the Ca2+-activated channel TRPM4 and it is more distantly related to the cold-activated channel TRPM8. In patch clamp recordings, TRPM5 channels are activated by micromolar concentrations of Ca2+ and are permeable to monovalent but not divalent cations. TRPM5 channel activity is strongly regulated by voltage, phosphoinositides and temperature, and is blocked by acid pH. Study of TRPM4 and TRPM8, which show similar modes of regulation, has yielded insights into possible structural domains of TRPM5. Understanding the structural basis for TRPM5 function will ultimately allow the design of pharmaceuticals to enhance or interfere with taste sensations. [ABSTRACT FROM AUTHOR]

TRPM6 and TRPM7 proteins share similar molecular structures and biophysical properties. Both proteins are Mg2+- and Ca2+-permeable cation channels with the typical topology of six transmembrane domains. In addition, TRPM6 and TRPM7 function as serine/threonine kinases with kinase domains at their C-terminal tails. At present, the role of the association of kinase and channel domains in TRPM6 and TRPM7 remains elusive. TRPM6 is mainly expressed in kidney and intestine, where it might be responsible for epithelial Mg2+ re/absorption. This hypothesis is strengthened by the identification of TRPM6 mutants in patients with a rare but severe hereditary disease called hypomagnesaemia with secondary hypocalcaemia. The aim of this review is to provide a brief but concise overview of the information currently available about TRPM6. [ABSTRACT FROM AUTHOR]

In the current review we will summarise data from the recent literature describing molecular and functional properties of TRPM4. Together with TRPM5, these channels are up till now the only molecular candidates for a class of non-selective, Ca2+-impermeable cation channels which are activated by elevated Ca2+ levels in the cytosol. Apart from intracellular Ca2+, TRPM4 activation is also dependent on membrane potential. Additionally, channel activity is modulated by ATP, phosphatidylinositol bisphosphate (PiP2), protein kinase C (PKC) phosphorylation and heat. The molecular determinants for channel activation, permeation and modulation are increasingly being clarified, and will be discussed here in detail. The physiological role of Ca2+-activated non-selective cation channels is unclear, especially in the absence of gene-specific knock-out mice, but evidence indicates a role as a regulator of membrane potential, and thus the driving force for Ca2+ entry from the extracellular medium. [ABSTRACT FROM AUTHOR]

TRPM3 is the last identified member of the TRPM subfamily and is most closely related to TRPM1. Due to alternative splicing, the TRPM3 gene encodes a large number of different variants. One splice event, affecting the pore-forming region of the channel, changes its selectivity for divalent cations. Inthis review, we give an overview of the identified TRPM3 variants and compare their functional properties. [ABSTRACT FROM AUTHOR]

TRPM2 is a cation channel enabling influx of Na+ and Ca2+, leading to depolarization and increases in the cytosolic Ca2+ concentration ([Ca2+]i). It is widely expressed, e.g. in many neurons, blood cells and the endocrine pancreas. Channel gating is induced by ADP-ribose (ADPR) that binds to a Nudix box motif in the cytosolic C-terminus of the channel. Endogenous ADPR concentrations in leucocytes are sufficiently high to activate TRPM2 in the presence of an increased [Ca2+]i but probably not at resting [Ca2+]i. Another channel activator is oxidative stress, especially hydrogen peroxide (H2O2) that may act through ADPR after ADPR polymers have been formed by poly(ADP-ribose) polymerases (PARPs) and hydolysed by glycohydrolases. H2O2-stimulated TRPM2 channels essentially contribute to insulin secretion in pancreatic β-cells and alloxan-induced diabetes mellitus. Inhibition of TRPM2 channels may be achieved by channel blockers such as flufenamic acid or the anti-fungal agents clotrimazole or econazole. Selective blockers of TRPM2 are not yet available; those would be valuable for a characterization of biological roles of TRPM2 in various tissues and as potential drugs directed against oxidative cell damage, reperfusion injury or leucocyte activation. Activation of TRPM2 may be prevented by anti-oxidants, PARP inhibitors and glycohydrolase inhibitors. In future, binding of ADPR to the Nudix box may be targeted. In light of the wide-spread expression and growing list of cellular functions of TRPM2, useful therapeutic applications are expected for future drugs that block TRPM2 channels or inhibit their activation. [ABSTRACT FROM AUTHOR]

Ca2+ homeostasis in the body is tightly controlled, and is a balance between absorption in the intestine, excretion via the urine, and exchange from bone. Recently, the epithelial Ca2+ channel (TRPV5) has been identified as the gene responsible for the Ca2+ influx in epithelial cells of the renal distal convoluted tubule. TRPV5 is unique within the family of transient receptor potential (TRP) channels due to its high Ca2+ selectivity. Ca2+ flux through TRPV5 is controlled in three ways. First, TRPV5 gene expression is regulated by calciotropic hormones such as vitamin D3 and parathyroid hormone. Second, Ca2+ transport through TRPV5 is controlled by modulating channel activity. Intracellular Ca2+, for example, regulates channel activity by feedback inhibition. Third, TRPV5 is controlled by mobilization of the channel through trafficking toward the plasma membrane. The newly identified anti-aging hormone Klotho regulates TRPV5 by cleaving off sugar residues from the extracellular domain of the protein, resulting in a prolonged expression of TRPV5 at the plasma membrane. Inactivation of TRPV5 in mice leads to severe hypercalciuria, which is compensated by increased intestinal Ca2+ absorption due to augmented vitamin D3 levels. Furthermore, TRPV5 deficiency in mice is associated with polyuria, urine acidification, and reduced bone thickness. Somepharmaceutical compounds, such as the immunosuppressant FK506, affect the Ca2+ balance by modulating TRPV5 gene expression. This underlines the importance of elucidating the role of TRPV5 in Ca2+-related disorders, thereby enhancing the possibilities for pharmacological intervention. This chapter describes a unique TRP channel and highlights its regulation and function in renal Ca2+ reabsorption and overall Ca2+ homeostasis. [ABSTRACT FROM AUTHOR]

The ion channel TRPV6 is likely to function as an epithelial calcium channel in organs with high calcium transport requirements such as the intestine, kidney, and placenta. Transcriptional regulation of TRPV6 messenger RNA (mRNA) is controlled by 1,25-dihydroxyvitamin D, which is the active hormonal form of vitamin D3, and by additional calcium-dependent and vitamin D3-independent mechanisms. Under physiological conditions, the conductance of the channel itself is highly calcium-selective and underlies complex inactivation mechanisms triggered by intracellular calcium and magnesium ions. There is growing evidence that transcriptional regulation of TRPV6 in certain tissues undergoing malignant transformation, such as prostate cancer, is linked to cancer progression. [ABSTRACT FROM AUTHOR]

TRPV4 is a non-selective cation channel subunit expressed in a wide variety of tissues. TRP channels are formed by a tetrameric complex of channel subunits. The available evidence suggests that TRPV4 cannot form heteromultimers with other TRPV isoforms, and that TRPV4-containing channels are homotetramers. These channels have a characteristic outwardly rectifying current-voltage relation, and are 5-10 times more permeable for Ca2+ than for Na+. TRPV4 can be activated by a wide range of stimuli including physical (cell swelling, heat, mechanical stimulation) and chemical stimuli (endocannabinoids, arachidonic acid, and, surprisingly, 4α-phorbol esters). Activation by swelling and endocannabinoids involves cytochrome P450 epoxygenase-dependent arachidonic acid metabolism to the epoxyeicosatrienoic acids (EETs). Heat and 4α-phorbol esters also seem to share a common mechanism of activation, but the endogenous messenger involved in the response to heat has not yet been identified. Ca2+ acting from the intracellular side can have both potentiating and inhibitory effects on channel activity and is involved in channel activation and inactivation. Given its wide expression and the variety of activatory stimuli, TRPV4 is likely to play a number of physiological roles. Studies with TRPV4-/- mice suggest a role for the channel in the regulation of body osmolarity, mechanosensation, temperature sensing, vascular regulation and, possibly, hearing. [ABSTRACT FROM AUTHOR]

2-Aminoethoxydiphenyl borate (2APB) had been depicted as a universal blocker of transient receptor potential (TRP) channels. While evidence has accumulated showing that some TRP channels are indeed inhibited by 2APB, especially in heterologous expression systems, there are other TRP channels that are unaffected or affected very little by this compound. More interestingly, the thermosensitive TRPV1, TRPV2, and TRPV3 channels are activated by 2APB. This has been demonstrated both in heterologous systems and in native tissues that express these channels. A number of 2APB analogs have been examined for their effects on native store-operated channels and heterologously expressed TRPV3. These studies revealed a complex mechanism of action for 2APB and its analogs on ion channels. In this review, we have summarized the current results on 2APB-induced activation of TRPV1-3 and discussed the potential mechanisms by which 2APB may regulate TRP channels. [ABSTRACT FROM AUTHOR]

TRPV1, the archetypal member of the vanilloid TRP family, was initially identified as the receptor for capsaicin, the pungent ingredient in hot chili peppers. The receptor has a diverse tissue distribution, with high expression in sensory neurons. TRPV1 is a nonselective cation channel with significant permeability to calcium, protons, and large polyvalent cations. It is the most polymodal TRP channel, being activated by numerous stimuli, including heat, voltage, vanilloids, lipids, and protons/cations. TRPV1 acts as a molecular integrator of physical and chemical stimuli in peripheral nociceptor terminals and plays a critical role in thermal inflammatory hyperalgesia. In addition, TRPV1 may regulate a variety of physiological functions in different organ systems. Various second messenger systems regulate TRPV1 activity, predominantly by serine-threonine phosphorylation. In this review, we provide a concise summary of the information currently available about this channel. [ABSTRACT FROM AUTHOR]

Canonical transient receptor potential 7 (TRPC7) is the seventh identified member of the mammalian TRPC channel family, comprising nonselective cation channels activated through the phospholipase C (PLC) signaling pathway. TRPC7 is directly activated by diacylglycerol (DAG), one of the PLC products, having high sequence homology with TRPC3 and TRPC6, which are also activated by DAG. TRPC7 shows unique properties of activation, such as constitutive activity and susceptibility to negative regulation by extracellular Ca2+. Although the physiological importance of TRPC7 in the native environment remains elusive, TRPC7 would play important roles in Ca2+ signaling pathway through these characteristic features. [ABSTRACT FROM AUTHOR]

TRPC6 is a Ca2+-permeable non-selective cation channel expressed in brain, smooth muscle containing tissues and kidney, as well as in immune and blood cells. Channel homomers heterologously expressed have a characteristic doubly rectifying current-voltage relationship and are six times more permeable for Ca2+ than for Na+. In smooth muscle tissues, however, Na+ influx and activation of voltage-gated calcium channels by membrane depolarization rather than Ca2+ elevation by TRPC6 channels is the driving force for contraction. TRPC6 channels are directly activated by the second messenger diacylglycerol (DAG) and regulated by specific tyrosine or serine phosphorylation. Extracellular Ca2+ has inhibitory effects, while Ca2+/calmodulin acting from the intracellular side has potentiator effects on channel activity. Given its specific expression, TRPC6 is likely to play a number of physiological roles. Studies with TRPC6-/- mice suggest a role for the channel in the regulation of vascular and pulmonary smooth muscle contraction. TRPC6 was identified as an essential component of the slit diaphragm architecture of kidney podocytes. Other functions in immune and blood cells, as well as in brain and in smooth muscle-containing tissues such as stomach, colon and myometrium, remain elusive. [ABSTRACT FROM AUTHOR]

Canonical transient receptor potential 5 TRPC5 (also TrpC5, trp-5 or trp5) is one of the seven mammalian TRPC proteins. Its known functional property is that of a mixed cationic plasma membrane channel with calcium permeability. It is active alone or as a heteromultimeric assembly with TRPC1; TRPC4 and TRPC3 may also be involved. Multiple activators of TRPC5 are emerging, including various G protein-coupled receptor agonists, lysophospholipids, lanthanide ions and, in some contexts, calcium store depletion. Intracellular calciumhas complex impact on TRPC5, including a permissive role for other activators, as well as inhibition at high concentrations. Protein kinase C is inhibitory and mediates desensitisation following receptor activation. Tonic TRPC5 activity is detected and may reflect the presence of constitutive activation signals. The channel has voltage dependence but the biological significance of this is unknown; it is partially due to intracellular magnesium blockade at aspartic acid residue 633. Protein partners include calmodulin, CaBP1, enkurin, Na+-H+ exchange regulatory factor (NHERF) and stathmin. TRPC5 is included in local vesicular trafficking regulated by growth factors through phosphatidylinositol (PI)-3-kinase, Rac1 and PIP-5-kinase. Inhibition of myosin light chain kinase suppresses TRPC5, possibly via an effect on trafficking. Biological roles of TRPC5 are emerging but more reports on this aspect are needed. One proposed role is as a mediator of calcium entry and excitation in smooth muscle, another as an inhibitor of neuronal growth cone extension. The latter is intriguing in view of the original cloning of the human TRPC5 gene from a region of the X chromosome linked to mental retardation. TRPC5 is a broadly expressed calcium channel with capability to act as an integrator of extracellular and intracellular signals at the level of calcium entry. [ABSTRACT FROM AUTHOR]

TRPC4 (transient receptor potential canonical 4) is a member of the TRPC subfamily and, within this sub-family, TRPC4 is most closely related to TRPC5. A number of splice variants of TRPC4 have been identified, whereby TRPC4α and TRPC4β appear to be the most abundant isoforms in various species. TRPC4α comprises six transmembrane segments and the N- and C-termini are located intracellularly. Additionally, TRPC4α shares other structural features with members of the TRPC sub-group, including ankyrin-like repeats, coiled-coil regions and binding sites for calmodulin and IP3 receptors. Three calmodulin-binding domains have been identified in the C-terminus of TRPC4α. TRPC4β lack 84 amino acids in the C-terminus, which correspond to the last two calmodulin-binding sites of TRPCα. The first and last calmodulin-binding domains of TRPC4α overlap with binding sites for the N- and C-termini of IP3 receptors. The ionic channels formed by TRPC4 appear to be Ca2+-permeable, although there is a considerably discrepancy in the degree of Ca2+ selectivity. Studies with mice lacking TRPC4 (TRPC4−/−) suggest an important role for TRPC4 in supporting Ca2+ entry. The defect in Ca2+ entry in TRPC4−/− mice appears to be associated with a reduction of the vasorelaxation of arteries, vascular permeability in the lung and neurotransmitter release from thalamic dendrites. [ABSTRACT FROM AUTHOR]

TRPC3 represents one of the first identified mammalian relatives of the Drosophila trp gene product. Despite intensive biochemical and biophysical characterization as well as numerous attempts to uncover its physiological role in native cell systems, this channel protein still represents one of the most enigmatic members of the transient receptor potential (TRP) superfamily. TRPC3 is significantly expressed in brain and heart and likely to play a role in both non-excitable as well as excitable cells, being potentially involved in a wide spectrum of Ca2+ signalling mechanisms. Its ability to associate with a variety of partner proteins apparently enables TRPC3 to form different cation channels in native cells. TRPC3 cation channels display unique gating and regulatory properties that allow for recognition and integration of multiple input stimuli including lipid mediators and cellular Ca2+ gradients as well as redox signals. The physiological/pathophysiological functions of this highly versatile cation channel protein are as yet barely delineated. Here we summarize current knowledge on properties and possible signalling functions of TRPC3 and discuss the potential biological relevance of this signalling molecule. [ABSTRACT FROM AUTHOR]

TRPC (canonical transient receptor potential) channels are the closest mammalian homologs of Drosophila TRP and TRP-like channels. TRPCs are rather nonselective Ca2+ permeable cation channels and affect cell functions through their ability to mediate Ca2+ entry into cells and their action to collapse the plasma membrane potentials. In neurons the latter function leads to action potentials. The mammalian genome codes for seven TRPCs of which TRPC2 is the largest with the most restricted pattern of expression and has several alternatively spliced variants. Expressed in model cells, TRPC2 mediates both receptor- and store depletion-triggered Ca2+ entry. TRPC2 is unique among TRPCs in that its complete gene has been lost from the Old World monkey and human genomes, in which its remnants constitute a pseudogene. Physiological roles for TRPC2 have been studied in mature sperm and the vomeronasal sensory system. In sperm, TRPC2 is activated by the sperm's interaction with the oocyte's zona pellucida, leading to entry of Ca2+ and activation of the acrosome reaction. In the vomeronasal sensory organ (VNO), TRPC2 was found to constitute the transduction channel activated through signaling cascade initiated by the interaction of pheromones with V1R and V2R G protein-coupled receptors on the dendrites of the sensory neurons. V1Rs and V2Rs, the latter working in conjunction with class I MHC molecules, activate Gi- and Go-type G proteins which in turn trigger activation of TRPC2, initiating an axon potential that travels to the axonal terminals. The signal is then projected to the glomeruli of the auxiliary olfactory bulb from where it is carried first to the amygdala and then to higher cortical cognition centers. Immunocytochemistry and gene deletion studies have shown that (1) the V2R-Go-MHCIb-β2m pathway mediates male aggressive behavior in response to pheromones; (2) the V1R-Gi2 pathway mediates mating partner recognition, and (3) these differences have an anatomical correlate in that these functional components are located in anatomically distinct compartments of the VNO. Interestingly, these anatomically segregated signaling pathways use a common transduction channel, TRPC2. [ABSTRACT FROM AUTHOR]

The full-length transient receptor (TRPC)1 polypeptide is composed of about 790 amino acids, and several splice variants are known. The predicted structure and topology is of an integral membrane protein composed of six transmembrane domains, and a cytoplasmic C- and N-terminal domain. The N-terminal domain includes three ankyrin repeat motifs. Antibodies which recognise TRPC1 have been developed, but it has been difficult to obtain antibodies which have high affinity and specificity for TRPC1. This has made studies of the cellular functions of TRPC1 somewhat difficult. The TRPC1 protein is widely expressed in different types of animal cells, and within a given cell is found at the plasma membrane and at intracellular sites. TRPC1 interacts with calmodulin, caveolin-1, the InsP3 receptor, Homer, phospholipase C and several other proteins. Investigations of the biological roles and mechanisms of action of TRPC1 have employed ectopic (over-expression or heterologous expression) of the polypeptide in addition to studies of endogenous TRPC1. Both approaches have encountered difficulties. TRPC1 forms heterotetramers with other TRPC polypeptides resulting in cation channels which are non-selective. TRPC1 may be: a component of the pore of store-operated Ca2+ channels (SOCs); a subsidiary protein in the pathway of activation of SOCs; activated by interaction with InsP3R; and/or activated by stretch. Further experiments are required to resolve the exact roles and mechanisms of activation of TRPC1. Cation entry through the TRPC1 channel is feed-back inhibited by Ca2+ through interaction with calmodulin, and is inhibited by Gd3+, La3+, SKF96365 and 2-APB, and by antibodies targeted to the external mouth of the TRPC1 pore. Activation of TRPC1 leads to the entry to the cytoplasmic space of substantial amounts of Na+ as well as Ca2+. A requirement for TRPC1 is implicated in numerous downstream cellular pathways. The most clearly described roles are in the regulation of growth cone turning in neurons. It is concluded that TRPC1 is a most interesting protein because of the apparent wide variety of its roles and functions and the challenges posed to those attempting to elucidate its primary intracellular functions and mechanisms of action. [ABSTRACT FROM AUTHOR]

The transient receptor potential (TRP) ion channels are named after the role of the channels in Drosophila phototransduction. Mammalian TRP channel subunit proteins are encoded by at least 28 genes. TRP cation channels display an extraordinary assortment of selectivities and activation mechanisms, some of which represent previously unrecognized modes of regulating ion channels. In addition, the biological roles of TRP channels appear to be equally diverse and range from roles in thermosensation and pain perception to Ca2+ and Mg2+ absorption, endothelial permeability, smooth muscle proliferation and gender-specific behaviour. [ABSTRACT FROM AUTHOR]

Heart failure associated with coronary artery disease is a major cause of morbidity and mortality. Recent developments in the understanding of the molecular mechanisms of heart failure have led to the identification of novel therapeutic targets which, combined with the availability of efficient gene delivery vectors, offer the opportunity for the design of gene therapies for protection of the myocardium. Viral-based therapies have been developed to treat polygenic and complex diseases such as myocardial ischaemia, hypertension, atherosclerosis and restenosis. Some of these experimental therapies are now undergoing clinical evaluation in patients with cardiovascular diseases. In this review we will focus on the latest advances in the field of gene therapy for treatment of heart failure and their clinical application. [ABSTRACT FROM AUTHOR]

Endothelial cells play a key role in the development and function of blood and lymph vessels. Excessive proliferation and transformation of endothelial cells lead to pathological angiogenesis/lymphangiogenesis or vascular malfunctions which are hallmarks of malignant disorders. There is emerging evidence that circulating endothelial progenitor cells (EPCs) also contribute significantly to these processes. Major progress has been achieved over the past few years in the identification of key molecules involved, and in targeting tumour angiogenesis for human therapy. Current research efforts are concentrated on deciphering the origin and functional properties of endotheliumin various tumours, as well as endothelial neoplasms themselves. The aim of these studies is to investigate the molecular mechanisms regulating mobilisation of EPCs from bone marrow, and their homing and differentiation into mature endotheliumin situ at sites of neovascularisation, as well as the role of viral oncogenes in regulating the plasticity and extending the life span of endothelial cells. Integrated understanding of the mechanisms regulating the properties and function of endothelial cells during tumourigenesis is resulting in the development of a number of exciting and bold approaches for the treatment of cancer. [ABSTRACT FROM AUTHOR]

Atherosclerosis depends critically on altered behavior of the intrinsic cells of the artery wall, the endothelial cells and smooth muscle cells, and inflammatory leukocytes that join them in the arterial intima during the atherogenic process. The homeostatic properties of the normal endothelium contribute importantly to maintenance of aspects of arterial health including the appropriate regulation of blood flow, a basal anti-inflammatory state, promotion of fibrinolysis while opposing blood coagulation, and control of the balance of cellular proliferation and death. Alterations in these endothelial homeostatic mechanisms contribute critically to atherogenesis, the progression of this disease, and ist complications. Recent advances have highlighted novel molecular mechanisms that regulate the atheroprotective functions of normal endothelial cells that go awry during atherogenesis. Therapeutic strategies that alter the course of atherosclerosis may act by combating endothelial dysfunction. [ABSTRACT FROM AUTHOR]

The vascular endothelium plays a fundamental role in the basal and dynamic regulation of the circulation. Thus, it has a crucial role in the pathogenesis of hypertension. A spectrum of vasoactive substances is synthesised in the endothelium; of these, nitric oxide (NO), prostacyclin (PGI2) and endothelin (ET)-1 are the most important. There is a continuous basal release of NO determining the tone of peripheral blood vessels. Systemic inhibition of NO synthesis or scavenging of NO through oxidative stress causes an increase in arterial blood pressure. Also, the renin-angiotensin-aldosterone system has a major role in hypertension as it has a direct vasoconstrictor effect and important interactions with oxygen free radicals and NO. Prostacyclin, in contrast to NO, does not contribute to the maintenance of basal vascular tone of conduit arteries, but its effect on platelets is most important. ET acts as the natural counterpart to endothelium-derived NO and has an arterial blood pressure-raising effect in man. Anti-hypertensive therapy lowers blood pressure and may influence these different mediators, thus influencing endothelial function. In summary, due to its position between the blood pressure and smooth muscle cells responsible for peripheral resistance, the endothelium is thought to be both victim and offender in arterial hypertension. The delicate balance of endothelium-derived factors is disturbed in hypertension. Specific anti-hypertensive and anti-oxidant treatment is able to restore this balance. [ABSTRACT FROM AUTHOR]

The wear and tear processes that are thought to contribute to human ageing may play an important role in the development of vascular diseases. One such process is cellular senescence. In endothelial cells the senescent phenotype can be induced by a number of factors, including telomere damage, oxidative stress and sustained mitogenic stimulation. Several lines of evidence indicate that endothelial cell senescence may be relevant to vascular disease. In this chapter we examine the causes, mechanisms and regulation of endothelial cell senescence as they emerge from studies in cell culture. We also describe the senescent phenotype and discuss its pathophysiological implications. We review the evidence for the occurrence of endothelial cell senescence in vivo and examine findings in animal models of ageing and human genetic disorders that argue for and against a role of endothelial cell senescence in age-related vascular pathology. Finally, we address the particular case of endothelial progenitor cell senescence and discuss the relevance of this phenomenon for angiogenesis and vascular repair. [ABSTRACT FROM AUTHOR]

The vasculature is the first organ to arise during development. Blood vessels run through virtually every organ in the body (except the avascular cornea and the cartilage), assuring metabolic homeostasis by supplying oxygen and nutrients and removing waste products. Not surprisingly therefore, vessels are critical for organ growth in the embryo and for repair of wounded tissue in the adult. Notably, however, an imbalance in angiogenesis (the growth of blood vessels) contributes to the pathogenesis of numerous malignant, inflammatory, ischaemic, infectious and immune disorders. During the last two decades, an explosive interest in angiogenesis research has generated the necessary insights to develop the first clinically approved anti-angiogenic agents for cancer and blindness. This novel treatment is likely to change the face of medicine in the next decade, as over 500 million people worldwide are estimated to benefit from pro- or anti-angiogenesis treatment. In this following chapter, we discuss general key angiogenic mechanisms in health and disease, and highlight recent developments and perspectives of anti-angiogenic therapeutic strategies. [ABSTRACT FROM AUTHOR]

Vascular endothelial cells (ECs) perform a number of functions required to maintain homeostasis. Inflammation can cause EC injury and death which disrupt these processes and result in endothelial dysfunction. Three common mediators of EC injury in inflammation are macrophage-derived cytokines, such as tumour necrosis factor (TNF); neutrophil-generated reactive oxygen species (ROS) and cytolytic T lymphocytes (CTL). Here we describe the distinct but overlapping biochemical pathways of injury elicited by these different agents. [ABSTRACT FROM AUTHOR]

The emigration of leucocytes into the tissue as a crucial step in the response to inflammatory signals has been acknowledged for more than 100 years. The endothelium does not only represent a mechanical barrier between blood and tissue, the circulatory system also connects different organ systems with each other, thus allowing the communication between remote systems. Leucocytes can function asmessengers and messages at the same time. Failure or dysregulation of leucocyte-endothelial communication can severely affect the integrity of the organism. The interaction between leucocytes and the vascular endotheliumhas been recognised as an attractive target for the therapy of numerous disorders and diseases, including excessive inflammatory responses and autoimmune diseases, both associated with enormous consequences for patients and the health care system. There is promising evidence that the success rate of such treatments will increase as the understanding of the molecular mechanisms keeps improving. This chapter reviews the current knowledge about leucocyte-endothelial interaction. It will also display examples of both physiological and dysregulated leucocyte-endothelial interactions and identify potential therapeutical approaches. [ABSTRACT FROM AUTHOR]

The functional phenotypic plasticity of the vascular endothelium relies on the ability of individual endothelial cells to integrate and transduce both humoral and biomechanical stimuli from their surrounding environments. Increasing evidence strongly suggests that biomechanical stimulation is a critical determinant of endothelial gene expression and the functional phenotypes displayed by these cells in several pathophysiological conditions. Herein we discuss the types of biomechanical forces that endothelial cells are constantly exposed to within the vasculature, explain how these biomechanical stimuli serve as regulators of endothelial functionanddiscuss the increasing evidence that "atherosclerosis-protective" or "atherosclerosis-prone" haemodynamic environments can beimportant causative factors for atherogenesis via the differential regulation of endothelial transcriptional programmes. [ABSTRACT FROM AUTHOR]

Major advances have been made over the last decade towards the elucidation of the molecular mechanisms involved in the endothelium-dependent regulation of vascular tone and blood flow. While the primary endothelium-derived vasodilator autacoid is nitric oxide, it is clear that epoxyeicosatrienoic acids and other endothelium-derived hyperpolarising factors, as well as endothelin-1 and reactive oxygen species, play a significant role in the regulation of vascular tone and gene expression. This review is intended as an overview of the signalling mechanisms that link haemodynamic stimuli (such as shear stress and cyclic stretch) and endothelial cell perturbation to the activation of enzymes generating vasoactive autacoids. [ABSTRACT FROM AUTHOR]

When the continuity of the vascular endothelium is disrupted, platelets and fibrin seal off the defect. Haemostatic processes are classified as primary (mainly involving platelets) and secondary (mainly related to fibrin formation or blood coagulation). When the blood clot is no longer required for haemostasis, the fibrinolytic system will dissolve it. The pivotal ligand for initial platelet recruitment to injured vessel wall components is von Willebrand factor (vWF), a multimeric protein present in the subendothelium and in plasma, where it is conformationally activated by shear forces. Adhering activated platelets recruit additional platelets, which are in turn activated and form a platelet aggregate. Coagulation is initiated by a reaction, activating factors IX and X. Once critical amounts of factor Xa are generated, thrombin generation is initiated and soluble fibrinogen is converted into insoluble fibrin. Excessive thrombin generation is prevented via inhibition by antithrombin and also via downregulation of its further generation by activation of the protein C pathway. Activation of the fibrinolytic system results from conversion of the proenzyme plasminogen into the active serine proteinase plasmin by tissue-type or urokinase-type plasminogen activators. Plasmin digests the fibrin component of a blood clot. Inhibition of the fibrinolytic system occurs at the level of the plasminogen activator (by plasminogen activator inhibitors) or at the level of plasmin (by α2-antiplasmin). Together, these physiological processes act to maintain normal functioning blood vessels and a non-thrombotic state. [ABSTRACT FROM AUTHOR]