TRP channels in lymphocytes

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.     

Vanilloid transient receptor potential cation channels: an overview

The mammalian branch of the Transient Receptor Potential (TRP) superfamily of cation channels consists of 28 members. They can be subdivided in six main subfamilies: the TRPC ('Canonical'), TRPV ('Vanilloid'), TRPM ('Melastatin'), TRPP ('Polycystin'), TRPML ('Mucolipin') and the TRPA ('Ankyrin') group. The TRPV subfamily comprises channels that are critically involved in nociception and thermo-sensing (TRPV1, TRPV2, TRPV3, TRPV4) as well as highly Ca2+ selective channels involved in Ca2+ absorption/reabsorption in mammals (TRPV5, TRPV6). In this review we summarize fundamental physiological properties of all TRPV members in the light of various cellular functions of these channels and their significance in the systemic context of the mammalian organism.     

Expression of multiple Transient Receptor Potential channel genes in murine 3T3-L1 cell lines and adipose tissue

BackgroundCalcium and its signaling have a role in adipogenesis. Transient Receptor Potential (TRP) channels are non-selective cation channels with a high permeability to calcium.MethodsIn the present study the expression of multiple TRP channels on mouse 3T3-L1 preadipocyte and adipocyte cells, white (WAT) and brown (BAT) adipose tissues was investigated using real time PCR (RT-PCR).ResultsTRPV1, TRPV3, TRPM8, TRPC4, TRPC6 were differentially expressed in preadipocytes and adipocytes suggesting their significance in adipogenesis. Genes for multiple TRP channels were also expressed in murineWAT and BAT, out of which TRPV4, TRPV6 and TRPC6 showed differential expression.ConclusionPresent study demonstrates the expression of TRP channels in mouse cell lines and adipose tissues.     

Activation of the melastatin-related cation channel TRPM3 by D-erythro-sphingosine [corrected

TRPM3, a member of the melastatin-like transient receptor potential channel subfamily (TRPM), is predominantly expressed in human kidney and brain. TRPM3 mediates spontaneous Ca2+ entry and nonselective cation currents in transiently transfected human embryonic kidney 293 cells. Using measurements with the Ca2+-sensitive fluorescent dye fura-2 and the whole-cell patch-clamp technique, we found that D-erythro-sphingosine, a metabolite arising during the de novo synthesis of cellular sphingolipids, activated TRPM3. Other transient receptor potential (TRP) channels tested [classic or canonical TRP (TRPC3, TRPC4, TRPC5), vanilloid-like TRP (TRPV4, TRPV5, TRPV6), and melastatin-like TRP (TRPM2)] did not significantly respond to application of sphingosine. Sphingosine-induced TRPM3 activation was not mediated by inhibition of protein kinase C, depletion of intracellular Ca2+ stores, and intracellular conversion of sphingosine to sphingosine-1-phosphate. Although sphingosine-1-phosphate and ceramides had no effect, two structural analogs of sphingosine, dihydro-D-erythro-sphingosine and N,N-dimethyl-D-erythro-sphingosine, also activated TRPM3. Sphingolipids, including sphingosine, are known to have inhibitory effects on a variety of ion channels. Thus, TRPM3 is the first ion channel activated by sphingolipids.     

Psychiatric Disorders and TRP Channels: Focus on Psychotropic Drugs

Psychiatric and neurological disorders are mostly associated with the changes in neural calcium ion signaling pathways required for activity-triggered cellular events. One calcium channel family is the TRP cation channel family, which contains seven subfamilies. Results of recent papers have discovered that calcium ion influx through TRP channels is important. We discuss the latest advances in calcium ion influx through TRP channels in the etiology of psychiatric disorders.Activation of TRPC4, TRPC5, and TRPV1 cation channels in the etiology of psychiatric disorders such as anxiety, fear-associated responses, and depression modulate calcium ion influx. Evidence substantiates that anandamide and its analog (methanandamide) induce an anxiolytic-like effect via CB1 receptors and TRPV1 channels. Intracellular calcium influx induced by oxidative stress has an significant role in the etiology of bipolar disorders (BDs), and studies recently reported the important role of TRP channels such as TRPC3, TRPM2, and TRPV1 in converting oxidant or nitrogen radical signaling to cytosolic calcium ion homeostasis in BDs. The TRPV1 channel also plays a function in morphine tolerance and hyperalgesia. Among psychotropic drugs, amitriptyline and capsazepine seem to have protective effects on psychiatric disorders via the TRP channels. Some drugs such as cocaine and methamphetamine also seem to have an important role in alcohol addiction and substance abuse via activation of the TRPV1 channel.Thus, we explore the relationships between the etiology of psychiatric disorders and TRP channel-regulated mechanisms. Investigation of the TRP channels in psychiatric disorders holds the promise of the development of new drug treatments.     

TRP channels in platelet function

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 P2(Xi) 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.     

TRPC3: a multifunctional, pore-forming signalling molecule

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.     

Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow

Members of the transient receptor potential (TRP) channel superfamily are present in vascular smooth muscle cells and play important roles in the regulation of vascular contractility. The TRPC3 and TRPC6 channels are activated by stimulation of several excitatory receptors in vascular smooth muscle cells. Activation of these channels leads to myocyte depolarization, which stimulates Ca2+ entry via voltage-dependent Ca2+ channels (VDCC), leading to vasoconstriction. The TRPV4 channels in arterial myocytes are activated by epoxyeicosatrienoic acids, and activation of the channels enhances Ca2+ spark and transient Ca2+-sensitive K+ channel activity, thereby hyperpolarizing and relaxing vascular smooth muscle cells. The TRPC6 and TRPM4 channels are activated by mechanical stimulation of cerebral artery myocytes. Subsequent depolarization and activation of VDCC Ca2+ entry is directly linked to the development of myogenic tone in vitro and to autoregulation of cerebral blood flow in vivo. These findings imply a fundamental importance of TRP channels in the regulation of vascular smooth muscle tone and suggest that TRP channels could be important targets for drug therapy under conditions in which vascular contractility is disturbed (e.g. hypertension, stroke, vasospasm).     

Newly emerging Ca2+ entry channel molecules that regulate the vascular tone

Local blood flow is critically determined by the arterial tone in which sustained Ca(2+) influx, activated by a variety of mechanisms, plays a central regulatory role. Recent progress in molecular biological research has disclosed unexpectedly diverse and complex facets of Ca(2+) entry channel molecules involved in this Ca(2+) influx. Candidates include several transient receptor potential (TRP) superfamily members such as TRPC1, TRPC4, TRPC6, TRPV2, TRPV4 and TRPM4, none of which exhibit simple properties attributable to a single particular role. Rather, they appear to be multimodally activated or modulated by receptor stimulation, temperature, mechanical stress or lipid second messengers generated from various sources, and may be involved in both acute vasomotor control and long-term vascular remodelling. This paper provides an overview of existing knowledge of TRP proteins, and their possible relationships with principal factors regulating the arterial tone (i.e., autonomic nerves, various autocrine and paracrine factors, and intravascular pressure).     

TRP channels in normal and dystrophic skeletal muscle

TRP proteins constitute non-selective cation-permeable ion channels, most of which are permeable to Ca2?. In skeletal muscle, several isoforms of the TRPC (Canonical), TRPV (Vanilloid) and TRPM (Melastatin) subfamilies are expressed. In particular, TRPC1, C3 and C6, TRPV2 and V4, TRPM4 and TRPM7 have been consistently found in cultured myoblasts or in adult muscles. These channels seem to directly or indirectly respond to membrane stretch or to Ca2? stores depletion; some isoforms might also constitute unregulated Ca2? leak channels. Their function is largely unknown. TRPC1 and C3 have been involved in muscle development, in particular in myoblasts migration and differentiation. TRPC1 and V4 might allow a basal influx of Ca2? at rest. Their lack has consequences on muscle fatigue. TRPV2 seems to be stretch-sensitive. It localizes mainly in intracellular pools at rest, and translocates to the plasma membrane upon IGF-1 stimulation. TRP channels seem to be involved in the pathophysiology of muscle disorders. In particular in Duchenne muscular dystrophy, the lack of the cytoskeletal protein dystrophin induces a disregulation of several ion channels leading to an abnormal influx of Ca2?. We discuss here, the possible involvement of TRP channels in this abnormal influx of Ca2?.     

Conservation of functional and pharmacological properties in the distantly related temperature sensors TRVP1 and TRPM8

Members of the transient receptor potential (TRP) superfamily of ion channels have now been defined as molecular transducers capable of reproducing the spectrum of temperature sensation exhibited by mammals. Because of their pivotal role in sensory transduction, many of these channels represent good targets for drug discovery. With a view to gaining further insight into the functional and pharmacological properties of these channels, we have used the whole-cell patch-clamp technique to study the human cold-sensitive menthol receptor transient receptor potential melastatin 8 (TRPM8) and compared its behavior with that of its distant relative, the heat-sensitive capsaicin-gated transient receptor potential vanilloid 1 (TRPV1). It is remarkable to find that TRPM8, in addition to its behavior as an outwardly rectifying, nonselective cation channel, shares many functional and pharmacological properties with TRPV1. TRPM8 exhibits prominent time- and voltage-dependent behavior, a property that may underlie the conserved rectification or gating mechanisms exhibited by these channels. We also show that TRPM8 is modulated by ethanol but unlike TRPV1 is insensitive to extracellular acidification. There is also significant overlap in the antagonist pharmacology of these channels with many TRPV1 antagonists such as capsazepine, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide (BCTC), (2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl)phenyl]-1-piperazinecarboxamide (CTPC), and N-(2-bromophenyl)-N'-{2-[ethyl(3-methylphenyl)amino]ethyl}-urea (SB-452533) exhibiting similar activity at TRPM8. Overall, the degree of pharmacological overlap between TRPV1 and TRPM8 has implications for the interpretation of studies conducted with these ligands to date and highlights a clear challenge for the design of selective TRP channel antagonists. Our finding that N-(3-methoxyphenyl)-4-chlorocinnamide (SB-366791), at least, represents an apparently selective antagonist for TRPV1 suggests that this goal is attainable.     

Agents in early development for treatment of bladder dysfunction – promise of drugs acting at TRP channels?

Introduction: In the lower urinary tract (LUT) several members of the TRP superfamily are involved in nociception and mechanosensory transduction. Animal studies have suggested a therapeutic potential of some of these channels, including TRPV1, TRPV4, TRPM8, TRPA1, and TRPM4, for treatment of bladder over- and underactivity and bladder pain disorders, but translation of this information to clinical application has been slow.

Areas covered: An update on and discussion of current information on the potential clinical use of TRP channel agonists/antagonists in the treatment of different types of bladder dysfunction. The electronic databases PubMed and Scopus were used to identify relevant clinical and animal studies.

Expert opinion: The therapeutic effect of TRPV1 channel desensitizing agonists (capsaicin, resiniferatoxin, given intravesically) has been convincingly demonstrated in some forms of bladder overactivity. However, so far, the potential of any of the small-molecule TRP channel blockers developed for non-bladder indications and tested in early human trials for safety has not been explored clinically in LUT dysfunction. The adverse effects of hyperthermia and reduction of noxious heat sensation of the first generation TRPV1 blockers have delayed development. Despite lack of translational information, TRP channels remain interesting targets for future LUT drugs.     

Newly emerging Ca2+ entry channel molecules that regulate the vascular tone

Local blood flow is critically determined by the arterial tone in which sustained Ca²⁺ influx, activated by a variety of mechanisms, plays a central regulatory role. Recent progress in molecular biological research has disclosed unexpectedly diverse and complex facets of Ca²⁺ entry channel molecules involved in this Ca²⁺ influx. Candidates include several transient receptor potential (TRP) superfamily members such as TRPC1, TRPC4, TRPC6, TRPV2, TRPV4 and TRPM4, none of which exhibit simple properties attributable to a single particular role. Rather, they appear to be multimodally activated or modulated by receptor stimulation, temperature, mechanical stress or lipid second messengers generated from various sources, and may be involved in both acute vasomotor control and long-term vascular remodelling. This paper provides an overview of existing knowledge of TRP proteins, and their possible relationships with principal factors regulating the arterial tone (i.e., autonomic nerves, various autocrine and paracrine factors, and intravascular pressure).     

TRP Channels in Respiratory Pathophysiology: The Role of Oxidative,Chemical Irritant and Temperature Stimuli

There is rapidly growing evidence indicating multiple and important roles of Ca²⁺-permeable cation TRP channels in the airways, both under normal and disease conditions. The aim of this review was to summarize the current knowledge of TRP channels in sensing oxidative, chemical irritant and temperature stimuli by discussing expression and function of several TRP channels in relevant cell types within the respiratory tract, ranging from sensory neurons to airway smooth muscle and epithelial cells. Several of these channels, such as TRPM2, TRPM8, TRPA1 and TRPV1, are discussed in much detail to show that they perform diverse, and often overlapping or contributory, roles in airway hyperreactivity, inflammation, asthma, chronic obstructive pulmonary disease and other respiratory disorders. These include TRPM2 involvement in the disruption of the bronchial epithelial tight junctions during oxidative stress, important roles of TRPA1 and TRPV1 channels in airway inflammation, hyperresponsiveness, chronic cough, and hyperplasia of airway smooth muscles, as well as TRPM8 role in COPD and mucus hypersecretion. Thus, there is increasing evidence that TRP channels not only function as an integral part of the important endogenous protective mechanisms of the respiratory tract capable of detecting and ensuring proper physiological responses to various oxidative, chemical irritant and temperature stimuli, but that altered expression, activation and regulation of these channels may also contribute to the pathogenesis of respiratory diseases.     

Transient receptor potential (TRP) channels in the airway: role in airway disease

Over the last few decades, there has been an explosion of scientific publications reporting the many and varied roles of transient receptor potential (TRP) ion channels in physiological and pathological systems throughout the body. The aim of this review is to summarize the existing literature on the role of TRP channels in the lungs and discuss what is known about their function under normal and diseased conditions. The review will focus mainly on the pathogenesis and symptoms of asthma and chronic obstructive pulmonary disease and the role of four members of the TRP family: TRPA1, TRPV1, TRPV4 and TRPM8. We hope that the article will help the reader understand the role of TRP channels in the normal airway and how their function may be changed in the context of respiratory disease.     

Identification of herbal components as TRPA1 agonists and TRPM8 antagonists

Transient receptor potential (TRP) channels are non-selective cation channels that are implicated in analgesia, bowel motility, wound healing, thermoregulation, vasodilation and voiding dysfunction. Many natural products have been reported to affect the activity of TRP channels. We hypothesize that numerous traditional herbal medicines (THMs) might exert their pharmacological activity through modulating the activity of TRP channels. The present study aimed to evaluate the effects of flavonoid aglycones and their glycosides, which are the main components of many THMs, on the TRP channel subtypes. A Ca²⁺ influx assay was performed using recombinant human TRPA1, TRPV1, TRPV4 and TRPM8 cell lines. Our findings showed that flavonoid aglycones and glycycoumarin activated TRPA1. In particular, isoflavone and chalcone compounds displayed potent TRPA1 agonistic activity. Furthermore, flavone aglycones showed concomitant potent TRPM8 inhibiting activity. Indeed, flavone, isoflavone aglycones, non-prenylated chalcones and glycycoumarin were found to be TRPM8 inhibitors. Hence, flavonoid aglycones metabolized by lactase-phlorizin hydrolase and β-glucosidase in the small intestine or gut microbiota of the large intestine could generate TRPA1 agonists and TRPM8 antagonists.

     

Emerging functions of 10 types of TRP cationic channel in vascular smooth muscle

1. The influx of Ca2+, Mg2+ and Na+ and the efflux of K+ have central importance for the function and survival of vascular smooth muscle cells, but progress in understanding the influx/efflux pathways has been restricted by a lack of identification of the genes underlying many of the non-voltage-gated cationic channels. 2. The present review highlights evidence suggesting the genes are mammalian homologues of the Transient Receptor Potential (TRP) gene of the fruit-fly Drosophila. The weight of evidence supports roles for TRPC1, TRPP2/1 and TRPC6, but recent studies point also to TRPC3, TRPC4/5, TRPV2, TRPM4 and TRPM7. 3. Activity of these TRP channels is suggested to modulate contraction and sense changes in intracellular Ca2+ storage, G-protein-coupled receptor activation and osmotic stress. Roles in relation to myogenic tone, actions of vasoconstrictors substances, Mg2+ homeostasis and the vascular injury response are suggested. 4. Knowledge that TRP channels are relevant to vascular smooth muscle cells in both their contractile and proliferative phenotypes should pave the way for a better understanding of vascular biology and provide the basis for the discovery of a new set of therapeutic agents targeted to vascular disease.     

TRP channels: potential drug target for neuropathic pain

Neuropathic pain is a debilitating disease which affects central as well as peripheral nervous system. Transient receptor potential (TRP) channels are ligand-gated ion channels that detect physical and chemical stimuli and promote painful sensations via nociceptor activation. TRP channels have physiological role in the mechanisms controlling several physiological responses like temperature and mechanical sensations, response to painful stimuli, taste, and pheromones. TRP channel family involves six different TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1) which are expressed in pain sensing neurons and primary afferent nociceptors. They function as transducers for mechanical, chemical, and thermal stimuli into inward currents, an essential first step for provoking pain sensations. TRP ion channels activated by temperature (thermo TRPs) are important molecular players in acute, inflammatory, and chronic pain states. Different degree of heat activates four TRP channels (TRPV1–4), while cold temperature ranging from affable to painful activate two indistinctly related thermo TRP channels (TRPM8 and TRPA1). Targeting primary afferent nociceptive neurons containing TRP channels that play pivotal role in revealing physical stimuli may be an effective target for the development of successful pharmacotherapeutics for clinical pain syndromes. In this review, we highlighted the potential role of various TRP channels in different types of neuropathic pain. We also discussed the pharmacological activity of naturally and synthetically originated TRP channel modulators for pharmacotherapeutics of nociception and neuropathic pain.     

Differential behavioral effect of the TRPM8/TRPA1 channel agonist icilin (AG-3-5)

Molecular identification of two new transient receptor potential (TRP) channels, TRPM8 and TRPA1, has prompted an intense interest in their functional roles. We report that an acute exposure to the TRPM8/TRPA1 agonist icilin (0.01-100 microM), but not TRPV1 agonist capsaicin (10 microM), causes an atypical dose-related increase in planarian motility. This is the first demonstration of a TRPM8/TRPA1 channel subtype agonist-induced differential pharmacological effect in invertebrates and provides a novel sensitive, quantifiable end-point for studying TRP channel pharmacology.