Involvement Of Transient Receptor Potential Channels Research Articles

Retinal TRP channels: Cell-type-specific regulators of retinal homeostasis and multimodal integration.

Transient receptor potential (TRP) channels are a widely expressed family of 28 evolutionarily conserved cationic ion channels that operate as primary detectors of chemical and physical stimuli and secondary effectors of metabotropic and ionotropic receptors. In vertebrates, the channels are grouped into six related families: TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP. As sensory transducers, TRP channels are ubiquitously expressed across the body and the CNS, mediating critical functions in mechanosensation, nociception, chemosensing, thermosensing, and phototransduction. This article surveys current knowledge about the expression and function of the TRP family in vertebrate retinas, which, while dedicated to transduction and transmission of visual information, are highly susceptible to non-visual stimuli. Every retinal cell expresses multiple TRP subunits, with recent evidence establishing their critical roles in paradigmatic aspects of vertebrate vision that include TRPM1-dependent transduction of ON bipolar signaling, TRPC6/7-mediated ganglion cell phototransduction, TRP/TRPL phototransduction in Drosophila and TRPV4-dependent osmoregulation, mechanotransduction, and regulation of inner and outer blood-retina barriers. TRP channels tune light-dependent and independent functions of retinal circuits by modulating the intracellular concentration of the 2nd messenger calcium, with emerging evidence implicating specific subunits in the pathogenesis of debilitating diseases such as glaucoma, ocular trauma, diabetic retinopathy, and ischemia. Elucidation of TRP channel involvement in retinal biology will yield rewards in terms of fundamental understanding of vertebrate vision and therapeutic targeting to treat diseases caused by channel dysfunction or over-activation.

Transient receptor potential channel involvement in antinociceptive effect of citral in orofacial acute and chronic pain models.

This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels.See also Figure 1(Fig. 1).

About the Cover

Next article FreeAbout the CoverPDFPDF PLUSFull Text Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinked InRedditEmailQR Code SectionsMoreThis issue’s cover shows clonal sea anemones Diadumene (Haliplanella) lineata. Sea anemones are sessile marine cnidarians. Cnidarians use organelles called nematocysts made and deployed by cnidocytes to capture and kill prey rapidly following sensory stimulation. When triggered, nematocysts deploy an eversible barbed tubule through which a venom is injected into prey. Backward-facing barbs and an anchoring mechanism on the tentacle combine to retain captured prey, while tentacles bearing prey bend toward the mouth for ingestion.Nematocyst discharge is under hierarchal control of two classes of chemoreceptors: vibration-sensitive mechanoreceptors (VSMs) and contact-sensitive mechanoreceptors (CSMs). Chemoreceptors and VSMs on two or more supporting cells adjacent to cnidocytes form cnidocyte-supporting cell complexes (CSCCs), the functional units of nematocyst discharge. Three types of CSCCs regulate nematocyst discharge in D. lineata: (i) Type As have associated NANA chemoreceptors that tune vibration-sensitive mechanoreceptors (VSMs) to the movements of swimming prey that, in turn, predispose CSMs to trigger; (ii) Type Bs are sensitized by N-acetylneuraminic acid (NANA) that predisposes triggering CSMs to physical contact; and (iii) Type C CSCCs are activated by physical stimulation of contact-sensitive mechanoreceptors. The CSMs and VSMs require extracellular calcium, and the delay from triggering to discharge is measured in milliseconds. Such features suggest mechanogated ion channels, features shared by several types of transient receptor potential (TRP) channels.On pages 48–61 of this issue, A. Nam, S. Quarshie, M. Kimble, and D. A. Hessinger test general and selective TRP channel blockers, using a quantitative prey killing assay to implicate a variety of TRP channels involved in nematocyst-mediated prey killing. They found that non-selective TRP blockers, such as gadolinium (Gd+3) and lanthanum (La+3), potently and broadly inhibit both nematocyst discharge and prey killing from Type Bs and Cs, which is consistent with TRP channel involvement. They then demonstrated that three selective TRPV4 blockers inhibited prey killing from vibration-sensitive Type A CSCCs. Their data implicate TRPV4-like channels in nematocyst discharge from vibration-sensitive Type As and pharmacologically distinct TRP channels in Type Bs and Cs.Credits: Photo of Diadumene lineata by David Reed, with permission. Available under Creative Commons License CC BY-NC-SA 2.0. Cover design: Olivia Kinker, University of Chicago Press. Next article DetailsFiguresReferencesCited by The Biological Bulletin Volume 242, Number 1February 2022 Published in association with the Marine Biological Laboratory Article DOIhttps://doi.org/10.1086/719750 Views: 936Total views on this site © 2022 The University of Chicago. All rights reserved.PDF download Crossref reports no articles citing this article.

Spontaneous excitatory transmission enhancement produced by linalool and its isomer geraniol in rat spinal substantia gelatinosa neurons - involvement of transient receptor potential channels

BackgroundMany of plant-derived compounds inhibiting nerve conduction enhance glutamatergic spontaneous excitatory transmission by activating transient receptor potential (TRP) channels in spinal substantia gelatinosa (SG) neurons that play a crucial role in regulating nociceptive transmission. Although (±)-linalool and its isomer geraniol having antinociceptive effects inhibit nerve conduction, it has not been examined yet how they affect excitatory transmission in SG neurons. We examined the effects of the compounds on action potential-independent spontaneous excitatory transmission with a focus on an involvement of TRP channels. MethodsThe whole-cell patch-clamp technique was applied to SG neurons in adult rat spinal cord slices. Results(±)-Linalool increased the frequency of spontaneous excitatory postsynaptic current (sEPSC) with a small increase in its amplitude. The (±)-linalool activity was sensitive to TRP vanilloid-1 (TRPV1) antagonist capsazepine and TRP ankyrin-1 (TRPA1) antagonist HC-030,031 while resistant to BCTC that is antagonist for cloned TRPV1 and TRP melastatin-8 (TRPM8) channels and for TRPM8 channels in the SG, indicating TRPV1 and TRPA1 activation. In 73% of the neurons tested, (±)-linalool produced an outward current at -70 mV. In SG neurons sensitive to (±)-linalool, geraniol produced a quantitatively similar effect to (±)-linalool. Geraniol-induced sEPSC frequency increase was sensitive to BCTC but resistant to capsazepine and HC-030,031, indicating TRPM8 activation. Outward currents produced by (±)-linalool and geraniol were unaffected by all of the TRP antagonists. ConclusionIn SG neurons, (±)-linalool and geraniol presynaptically enhanced spontaneous excitatory transmission by activating different types of TRP channel while hyperpolarizing membranes in a manner independent of TRP channels. Such a TRP channel modulation and hyperpolarization could contribute to the antinociceptive effects of (±)-linalool and geraniol.

Functional Importance of Transient Receptor Potential (TRP) Channels in Neurological Disorders.

Transient receptor potential (TRP) channels are transmembrane protein complexes that play important roles in the physiology and pathophysiology of both the central nervous system (CNS) and the peripheral nerve system (PNS). TRP channels function as non-selective cation channels that are activated by several chemical, mechanical, and thermal stimuli as well as by pH, osmolarity, and several endogenous or exogenous ligands, second messengers, and signaling molecules. On the pathophysiological side, these channels have been shown to play essential roles in the reproductive system, kidney, pancreas, lung, bone, intestine, as well as in neuropathic pain in both the CNS and PNS. In this context, TRP channels have been implicated in several neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and epilepsy. Herein, we focus on the latest involvement of TRP channels, with a special emphasis on the recently identified functional roles of TRP channels in neurological disorders related to the disruption in calcium ion homeostasis.

Gastrointestinal motility modulation by stress is associated with reduced smooth muscle contraction through specific transient receptor potential channel.

Excessive stress response causes disability in social life. There are many diseases caused by stress, such as gastrointestinal motility disorders, depression, eating disorders, and cardiovascular diseases. Transient receptor potential (TRP) channels underlie non-selective cation currents and are downstream effectors of G protein-coupled receptors. Ca2+ influx is important for smooth muscle contraction, which is responsible for gastrointestinal motility. Little is known about the possible involvement of TRP channels in the gastrointestinal motility disorders due to stress. The purpose of this study was to measure the changes in gastrointestinal motility caused by stress and to elucidate the mechanism of these changes. The stress model used the water immersion restraint stress. Gastrointestinal motility, especially the ileum, was recorded responses to electric field stimulation (EFS) by isometric transducer. EFS-induced contraction was significantly reduced in the ileum of stressed mouse. Even under the conditions treated with atropine, EFS-induced contraction was significantly reduced in the ileum of stressed mouse. In addition, carbachol-induced, neurokinin A-induced, and substance P-induced contractions were all significantly reduced in the ileum of stressed mouse. Furthermore, the expression of TRPC3 was decreased in the ileum of stressed mouse. These results suggest that the gastrointestinal motility disorders due to stress is associated with specific non-selective cation channel.

Emerging Perspectives on Pain Management by Modulation of TRP Channels and ANO1

Receptor-type ion channels are critical for detection of noxious stimuli in primary sensory neurons. Transient receptor potential (TRP) channels mediate pain sensations and promote a variety of neuronal signals that elicit secondary neural functions (such as calcitonin gene-related peptide [CGRP] secretion), which are important for physiological functions throughout the body. In this review, we focus on the involvement of TRP channels in sensing acute pain, inflammatory pain, headache, migraine, pain due to fungal infections, and osteo-inflammation. Furthermore, action potentials mediated via interactions between TRP channels and the chloride channel, anoctamin 1 (ANO1), can also generate strong pain sensations in primary sensory neurons. Thus, we also discuss mechanisms that enhance neuronal excitation and are dependent on ANO1, and consider modulation of pain sensation from the perspective of both cation and anion dynamics.

In vivo and ex vivo imaging of nociceptor expression and activity

Our ability to perceive nociceptive pain is crucial to respond to harmful stimuli: it warns us about noxiously hot or cold objects. Sensory nerve endings that respond to pain (nociceptors) initiate an electrical signal in the periphery and transport it to the dorsal horn and eventually to higher brain centers. The detection of noxious stimuli involves the expression of nociceptive ion channels in sensory nerve endings, such as transient receptor potential (TRP) channels. Recently we found that the acute response to noxious heat relies on the functional expression of TRPV1, TRPM3 and TRPA1 in sensory nerve endings. Calcium imaging on isolated dorsal root ganglia (DRG) is a widely accepted model to study the involvement of TRP channels in acute pain responses. However, DRGs are clusters of nerve cell bodies, present in the dorsal root of spinal nerves, far away from the skin where the physiological stimulus detection take place. We use two different optical measurement protocols to study ion channel activity in sensory neurons: an in vivo-protocol to image DRGs and an in tissue-protocol to visualize intact skin measurements. A cre-dependent GCaMP3 mouse line is used. These mice express the genetically encoded calcium indicator GCaMP3 in specific somatosensory neurons. Using this technique, we study the role of TRP channels in different pain models, such as inflammation.&amp;nbsp;

A TR(i)P to Cell Migration: New Roles of TRP Channels in Mechanotransduction and Cancer.

Cell migration is a key process in cancer metastasis, allowing malignant cells to spread from the primary tumor to distant organs. At the molecular level, migration is the result of several coordinated events involving mechanical forces and cellular signaling, where the second messenger Ca2+ plays a pivotal role. Therefore, elucidating the regulation of intracellular Ca2+ levels is key for a complete understanding of the mechanisms controlling cellular migration. In this regard, understanding the function of Transient Receptor Potential (TRP) channels, which are fundamental determinants of Ca2+ signaling, is critical to uncovering mechanisms of mechanotransduction during cell migration and, consequently, in pathologies closely linked to it, such as cancer. Here, we review recent studies on the association between TRP channels and migration-related mechanotransduction events, as well as in the involvement of TRP channels in the migration-dependent pathophysiological process of metastasis.

Involvement of TRP channels on fibromyalgiainduced pain

Fibromyalgia (FM) is a common chronic pain syndrome affecting up to 2% of the adult population.Several factors such as excessive oxidative stress and overload calcium ion (Ca2+) influx play main roles in the etiology of FM. Several pharmaceutical drugs such as antidepressants and voltage-gated calcium channel blockers are recommended for the treatment of FM; however, they fail to produce a satisfactory response in patients with FM because of the unclear etiology of the disease. Transient receptor potential (TRP) channels have six subfamilies and 27 members in human. Most of these channels are responsible in dorsal root ganglia (DRG) neurons for the Ca2+ permeation especially in neuronal cells. Expression level of the TRPM2 and TRPV1 channels are high in the DRG neurons and they show oxidative stress dependent activation (Tan and McNaughton 2016; Santos et al. 2018). The TRPM2 and TRPV1 channel expression levels in the DRG increased in different types of pain. Selenium as an antioxidant trace element is implicated as a neuroprotective agent in peripheral pain through the inhibition of apoptosis and regulation of the TRPM2 and TRPV1 channels (Kahya et al. 2017). Since a decade, a recent theory have argued that both supporting of intracellular antioxidant system and extracellular antioxidant administration may helpful in fibromyalgia for the inhibition of TRP channels mediated Ca2+ influx (Yüksel et al. 2017). In the oral presentation, I discussed novel effects of selenium on the treatment of irregular oxidative status and fibromyalgia by the regulation of TRPM2 and TRPV1 channels in rats. In conclusion, present literature information indicated that protective effects of selenium on TRPM2 and TRPV1 channels may novel approach to treat FM induced pain and mitochondrial oxidative stress. However, the subject should be clarified by further studies.

TRPs in Tox: Involvement of Transient Receptor Potential-Channels in Chemical-Induced Organ Toxicity-A Structured Review.

Chemicals can exhibit significant toxic properties. While for most compounds, unspecific cell damaging processes are assumed, a plethora of chemicals exhibit characteristic odors, suggesting a more specific interaction with the human body. During the last few years, G-protein-coupled receptors and especially chemosensory ion channels of the transient receptor potential family (TRP channels) were identified as defined targets for several chemicals. In some cases, TRP channels were suggested as being causal for toxicity. Therefore, these channels have moved into the spotlight of toxicological research. In this review, we screened available literature in PubMed that deals with the role of chemical-sensing TRP channels in specific organ systems. TRPA1, TRPM and TRPV channels were identified as essential chemosensors in the nervous system, the upper and lower airways, colon, pancreas, bladder, skin, the cardiovascular system, and the eyes. Regarding TRP channel subtypes, A1, M8, and V1 were found most frequently associated with toxicity. They are followed by V4, while other TRP channels (C1, C4, M5) are only less abundantly expressed in this context. Moreover, TRPA1, M8, V1 are co-expressed in most organs. This review summarizes organ-specific toxicological roles of TRP channels.

Role of TRP Channels in Dinoflagellate Mechanotransduction.

Transient receptor potential (TRP) ion channels are common components of mechanosensing pathways, mainly described in mammals and other multicellular organisms. To gain insight into the evolutionary origins of eukaryotic mechanosensory proteins, we investigated the involvement of TRP channels in mechanosensing in a unicellular eukaryotic protist, the dinoflagellate Lingulodinium polyedra. BLASTP analysis of the protein sequences predicted from the L. polyedra transcriptome revealed six sequences with high similarity to human TRPM2, TRPM8, TRPML2, TRPP1, and TRPP2; and characteristic TRP domains were identified in all sequences. In a phylogenetic tree including all mammalian TRP subfamilies and TRP channel sequences from unicellular and multicellular organisms, the L. polyedra sequences grouped with the TRPM, TPPML, and TRPP clades. In pharmacological experiments, we used the intrinsic bioluminescence of L. polyedra as a reporter of mechanoresponsivity. Capsaicin and RN1734, agonists of mammalian TRPV, and arachidonic acid, an agonist of mammalian TRPV, TRPA, TRPM, and Drosophila TRP, all stimulated bioluminescence in L. polyedra. Mechanical stimulation of bioluminescence, but not capsaicin-stimulated bioluminescence, was inhibited by gadolinium (Gd3+), a general inhibitor of mechanosensitive ion channels, and the phospholipase C (PLC) inhibitor U73122. These pharmacological results are consistent with the involvement of TRP-like channels in mechanosensing by L. polyedra. The TRP channels do not appear to be mechanoreceptors but rather are components of the mechanotransduction signaling pathway and may be activated via a PLC-dependent mechanism. The presence and function of TRP channels in a dinoflagellate emphasize the evolutionary conservation of both the channel structures and their functions.

Role of TRP ion channels in cancer and tumorigenesis.

Transient receptor potential (TRP) channels are recently identified proteins that form a versatile family of ion channels, the majority of which are calcium permeable and exhibit complex regulatory patterns with sensitivity to multiple environmental factors. While this sensitivity has captured early attention, leading to recognition of TRP channels as environmental and chemical sensors, many later studies concentrated on the regulation of intracellular calcium by TRP channels. Due to mutations, dysregulation of ion channel gating or expression levels, normal spatiotemporal patterns of local Ca(2+) distribution become distorted. This causes deregulation of downstream effectors sensitive to changes in Ca(2+) homeostasis that, in turn, promotes pathophysiological cancer hallmarks, such as enhanced survival, proliferation and invasion. These observations give rise to the appreciation of the important contributions that TRP channels make to many cellular processes controlling cell fate and positioning these channels as important players in cancer regulation. This review discusses the accumulated scientific knowledge focused on TRP channel involvement in regulation of cell fate in various transformed tissues.

Broad-range TRP channel inhibitors (2-APB, flufenamic acid, SKF-96365) affect differently contraction of resistance and conduit femoral arteries of rat

Transient receptor potential (TRP) channels are proposed to contribute to membrane depolarization and Ca2+ influx into vascular smooth muscle (VSM) cells. Our aim was to study the effects of widely used broad-range TRP channel inhibitors – 2-aminoethoxydiphenyl borate (2-APB), flufenamic acid (FFA) and SKF-96365 – on the contraction of freshly isolated small and large arteries.Endothelium-denuded resistance (≈250µm) and conduit (≈1000µm) femoral arteries were isolated from adult Wistar rats and mounted in wire myograph. The effects of the above mentioned TRP channel inhibitors and voltage-dependent calcium channel inhibitor nifedipine were studied on arterial contractions induced by phenylephrine, U-46619 or K+. Phenylephrine-induced contractions were also studied in the absence of extracellular Na+. mRNA expression of particular canonical and melastatin TRP channel subunits in femoral vascular bed was determined.TRP channel inhibitors attenuated K+-induced contraction less than nifedipine. Phenylephrine-induced contraction was more influenced by 2-APB in resistance arteries, while FFA completely prevented U-46619-induced contraction in both sizes of arteries. The absence of extracellular Na+ prevented the inhibitory effects of 2-APB, but not those of FFA.The observed effects of broad-range TRP channel inhibitors, which were dependent on the size of the artery, confirmed the involvement of TRP channels in agonist-induced contractions. The inhibitory effects of 2-APB (but not those of FFA or SKF-96365) were dependent on the presence of extracellular Na+.

TRPs and pain.

Nociception is the process of transmission of painful signals by nociceptors in the primary afferent nerve fibers, which specifically respond to noxious stimuli. These noxious stimuli are detected by nociceptors and converted into electrical signals, which are then transmitted to the spinal cord, thalamus, and the cerebral cortex, where pain is finally sensed. Transient receptor potential (TRP) ion channels have emerged as a family of evolutionarily conserved ligand-gated ion channels that function as molecular detectors of physical stimuli. Several member of this family, at least six channels from three TRP family subtypes (TRPV1-4, TRPM8, and TRPA1), are expressed in nociceptors, where they act as transducers for signals from thermal, chemical, and mechanical stimuli and play crucial roles in the generation and development of pathological pain perception. This review focuses on the increasing evidence of TRP channel involvement and contribution in nociceptive pain and the pain hypersensitivity associated with peripheral inflammation or neuropathy, and on the renewed interest in targeting TRP channels for pain relief.

Possible Involvement of TRP Channels in Cardiac Hypertrophy and Arrhythmia

Over the past 20 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge regarding the molecular basis of Ca2+ signals in cardiac myocytes. The functional significance of cardiac TRP channels is likely connected to the alteration of membrane potential or Ca2+ entry into a noncontractile compartment, where gene expression responsible for various cardiac diseases is induced. This review highlights some aspects of TRP channels with anticipated roles in cardiac disease. Evidence suggests that (a) increased activities of TRPC1, TRPC3, or TRPC6 are involved in the development of cardiac hypertrophy, where these TRPC channels act as unique sensors for a wide range of hypertrophic stimuli, and (b) mutations in TRPM4 are now recognized as causes of human cardiac conduction disorders. Ultimately, TRP channels may become novel pharmacological targets in the treatment of human cardiac disease.

Role of transient receptor potential channels in adipocyte biology

The transient receptor potential (TRP) channel superfamily is a family of 28 nonselective cation channels expressed on the plasma membrane with a high permeability to calcium. Role of TRP channels, especially TRP vanilloid 1, TRP ankyrin 1 and TRP melastatin 8, is widely documented in nociception. During the last few years, there has been a consistent increase in reports indicating the presence and significance of these channels in different tissues including bladder, skin, respiratory system and brain. Based on calcium permeability of these channels and the much published role of calcium and its signaling in adipogenesis, there is a potential for importance of these ion channels in adipocyte biology. This review provides insight into the involvement of TRP channels in adipocyte differentiation, obesity and associated complications. Furthermore, the authors will focus to evaluate these channels as potential therapeutic targets for the management of obesity.

Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

The functional roles of transient receptor potential (TRP) channels in the gastrointestinal tract have garnered considerable attention in recent years. We previously reported that daikenchuto (TU-100), a traditional Japanese herbal medicine, increased intestinal blood flow (IBF) via adrenomedullin (ADM) release from intestinal epithelial (IE) cells (Kono T et al. J Crohns Colitis 4: 161-170, 2010). TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders.

The Involvement of TRP Channels in Bone Homeostasis

Calcium and bone homeostasis are intimately related. On the one hand, bone relies on a sufficient supply of calcium to maintain its structural and mechanical properties and thus largely depends on calcium absorption in the intestine and calcium reabsorption in the kidney. On the other hand, bone serves as a calcium reserve from which calcium is mobilized to maintain normal calcium levels in blood. A negative external calcium balance will therefore at all times impair skeletal integrity. In addition to the external calcium balance, skeletal homeostasis also depends on the proper differentiation and functioning of bone cells, which relies for a large part on intracellular Ca2+ signaling. Members of the transient receptor potential (TRP) family of ion channels affect skeletal homeostasis by mediating processes involved in the extracellular as well as intracellular Ca2+ balance, including intestinal calcium absorption (TRPV6), renal calcium reabsorption (TRPV5), and differentiation of osteoclasts (TRPV1, TRPV2, TRPV4, TRPV5), chondrocytes (TRPV4), and possibly osteoblasts (TRPV1). In this review, we will give a brief overview of the systemic calcium homeostasis and the intracellular Ca2+ signaling in bone cells with special focus on the TRP channels involved in these processes.

Involvement of TRP channels in the CO2 chemosensitivity of locus coeruleus neurons

Catecholaminergic neurons in the locus coeruleus (LC) play a role in the ventilatory response to hypercapnia. Here, we show evidence for the involvement of transient receptor potential (TRP) channels. We found that the input resistance was reduced during an exposure to 8% CO(2) in ~35% LC neurons in mouse brain slices, accompanied by depolarization and higher firing activity. The neuronal responses suggest the opening of Na(+) or nonselective cationic channels instead of the closure of K(+) channels. As a major group of cationic channels, the TRP channels are expressed in the brain, some of which are activated by acidic pH. We therefore screened all representative TRP channels using the quantitative real-time PCR analysis. High levels of mRNA expression of TRPC5, TRPM2, and TRPM7 were found in the LC tissue. Of them, the TRPC5 transcript was the most abundant. The TRPC5 channel was activated by extracellular acidification when expressed in human embryonic kidney (HEK) cells. The TRPC5 currents started to be activated at pH 7.4 with pKa 6.9. The TRPC5 currents were also activated by isohydric hypercapnic and intracellular acidosis in a Ca(2+)-dependent manner. Consistently, the LC neurons were stimulated by both extra- and intracellular acidosis. The stimulatory effect of hypercapnia on LC neurons was eliminated by selective TRPC inhibitor SKF-96365 with and without the blockade of synaptic transmission. Single-cell PCR analysis indicated that TRPC5 mRNAs existed in the LC neurons. Thus these results strongly suggest that the TRP channels are likely to play a role in the CO(2) chemosensitivity of LC neurons, especially TRPC5.