TRP channels and mice deficient in TRP channels

Transient receptor potential (TRP) channels are a superfamily of functionally versatile cation-permeant ion channels present in almost all mammalian cell types. Although they were initially proposed as store-operated calcium channels, recent progress shows that they exhibit a variety of regulatory and functional themes. Here, we summarize the most salient features of TRP channels, the approaches that are providing meaningful discoveries, and the challenges ahead. We primarily emphasize the understanding gleaned from mouse models engineered to be deficient in various members of TRP superfamily and from the human patients that suffer clinically due to defects in TRP channels.     

Role of renal TRP channels in physiology and pathology

Kidneys critically contribute to the maintenance of whole-body homeostasis by governing water and electrolyte balance, controlling extracellular fluid volume, plasma osmolality, and blood pressure. Renal function is regulated by numerous systemic endocrine and local mechanical stimuli. Kidneys possess a complex network of membrane receptors, transporters, and ion channels which allows responding to this wide array of signaling inputs in an integrative manner. Transient receptor potential (TRP) channel family members with diverse modes of activation, varied permeation properties, and capability to integrate multiple downstream signals are pivotal molecular determinants of renal function all along the nephron. This review summarizes experimental data on the role of TRP channels in a healthy mammalian kidney and discusses their involvement in renal pathologies.     

Role of ion channels in lymphocytes

Summary Ion channels, and ion fluxes in general, appear to regulate a wide variety of processes important to lymphocyte function in normal and disease states. These include resting ionic homeostasis and the more complex signaling events involved in activation, proliferation, cytotoxic function, and volume regulation. The wider application of patch-clamp and microfluorimetry techniques to lymphocytes has helped to clarify some issues and raised many more. It seems likely that rapid progress will be made in our understanding of these areas through a combination of immunological, biochemical, and electrophysiological approaches.     

Drosophila TRP channels

The transient receptor potential (TRP) superfamily comprises a large group of related cation channels that display surprising diversity in the specific modes of activation and cation selectivities. However, a unifying theme is that many TRP channels play important roles in sensory physiology. The superfamily includes 28 mammalian members, which are subdivided into multiple subfamilies. Each of these subfamilies is represented by at least one of the 13 members in Drosophila, suggesting common evolutionary relationships. In recent years it has become clear that TRP channels in flies and mammals participate in similar sensory modalities. These include, but are not limited to, hearing, thermosensation, and certain specialized types of vision. With the recent flurry of new studies, 9 out of the 13 TRPs have been addressed in various contexts. As a result, the repertoire of biological roles attributed to Drosophila TRPs has increased considerably and is likely to lead to many additional surprises over the next few years.     

TRP离子通道

钙离子作为一种第二信使，在许多细胞功能中发挥着重要作用。短期的，如递质、腺体分泌，肌肉收缩；长期的，如细胞分化、程序死亡等。正常细胞都有一套完善的体系来维持钙的内稳定平衡。内质网／肌浆网的钙释放和来自质膜上钙通道的钙流入升高胞浆钙，而同时位于这两个部位的Ca^2 —泵也不断地将胞浆钙储存回钙库或泵出胞外。质膜上     

Umbellulone modulates TRP channels

Inhalation of umbellulone (UMB), the offensive principle of the so-called “headache tree” (California bay laurel, Umbellularia californica Nutt.), causes a painful cold sensation. We therefore studied the action of UMB and some derivatives devoid of thiol-trapping properties on the “cold” transient receptor potential cation channels TRPA1 and TRPM8. UMB activated TRPA1 in a dose-dependent manner that was attenuated by cysteine-to-serine isosteric mutation in TRPA1 (C622S), while channel block was observed at higher concentration. However, although activation by mustard oil was completely prevented in these mutants, UMB still retained activating properties, indicating that it acts on TRPA1 only as a partial electrophilic agonist. UMB also activated TRPM8, but to a lower extent than TRPA1. Removing Michael acceptor properties of UMB (reduction or nucleophilic trapping) was detrimental for the activation of TRPA1, but increased the blocking potency. This was, however, attenuated by acetylation of the hydroxylated analogs. All UMB derivatives, except the acetylated derivatives, were also TRPM8 activators. They acted, however, in a bimodal manner, inhibiting the channel more potently than UMB, and with tetrahydro-UMB being the most potent TRPM8 activator. In conclusion, UMB is a bimodal activator of TRPA1 and a weak activator of TRPM8. Non-electrophilic derivatives of UMB are better TRPM8 activators than the natural product and also potent blockers of this channel as well as of TRPA1. The lack of effects of the acetylated UMB derivatives suggests that steric hindrance may prevent access to the recognition site for the bicyclic monoterpene pharmacophore on TRPA1 and TRPM8.     

The role of chemosensitive afferent nerves and TRP ion channels in the pathomechanism of headaches

The involvement of trigeminovascular afferent nerves in the pathomechanism of primary headaches is well established, but a pivotal role of a particular class of primary sensory neurons has not been advocated. This review focuses on the evidence that supports the critical involvement of transient receptor potential (TRP) channels in the pathophysiology of primary headaches, in particular, migraine. Transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 receptors sensitive to vanilloids and other irritants are localized on chemosensitive afferent nerves, and they are involved in meningeal nociceptive and vascular responses involving neurogenic dural vasodilatation and plasma extravasation. The concept of the trigeminal nocisensor complex is put forward which involves the trigeminal chemosensitive afferent fibers/neurons equipped with specific nocisensor molecules, the elements of the meningeal microcirculatory system, and the dural mast cells. It is suggested that the activation level of this complex may explain some of the specific features of migraine headache. Pharmacological modulation of TRP channel function may offer a novel approach to the management of head pain, in particular, migraine.     

TRP channels in Drosophila photoreceptor cells

TRP cation channels are conserved throughout animal phylogeny and include many members that function in sensory physiology. The founding TRP is required for Drosophila phototransduction and has served as a paradigm for unravelling the roles and macromolecular organizations of TRP channels in native tissues. Two other TRPC channels, TRPL and TRPγ, are expressed in photoreceptor cells and form heteromultimers with TRP and with each other. TRP is a member of a supramolecular signalling complex, the signalplex, which includes the PDZ scaffold protein, INAD, and two other core members that remain bound and depend on INAD for localization. Other INAD binding proteins are proposed to interact dynamically with INAD, one of which, TRPL, undergoes light-dependent translocation in photoreceptor cells. Surprisingly, TRP has non-channel functions, including an anchoring role necessary for retaining INAD in the rhabdomeres. Loss of TRP function or constitutive TRP activity results in retinal degeneration, which can be suppressed by disruption or overexpression of the Na⁺/Ca²⁺ exchanger, CalX, respectively. Given that hypoxia-induced constitutive activity of some mammalian TRPs leads to neuronal cell death, interventions that increase Na⁺/Ca²⁺ exchanger or decrease TRP function have the potential to reduce the severity of cell death due to ischaemia.     

TRP channels and their implications in metabolic diseases

The transient receptor potential (TRP) channel superfamily is composed of 28 nonselective cation channels that are ubiquitously expressed in many cell types and have considerable functional diversity. Although changes in TRP channel expression and function have been reported in cardiovascular disease and renal disorders, the pathogenic roles of TRP channels in metabolic diseases have not been systemically reviewed. In this review, we summarised the distribution of TRP channels in several metabolic tissues and discussed their roles in mediating and regulating various physiological and pathophysiological metabolic processes and diseases including diabetes, obesity, dyslipidaemia, metabolic syndrome, atherosclerosis, metabolic bone diseases and electrolyte disturbances. This review provides new insight into the involvement of TRP channels in the pathogenesis of metabolic disorders and implicates these channels as potential therapeutic targets for the management of metabolic diseases.     

Potential role of transient receptor potential (TRP) channels in bladder cancer cells

Transient receptor potential (TRP) channels play important roles in thermal, chemical, and mechanical sensation in various tissues. In this study, we investigated the differences in urothelial TRP channels between normal urothelial cells and bladder cancer cells. TRPV2 and TRPM7 expression levels and TRPV2 activator-induced intracellular Ca²⁺ increases were significantly higher, whereas TRPV4 expression and TRPV4 activator-induced intracellular Ca²⁺ increases were significantly lower in mouse bladder cancer (MBT-2) cells compared to normal mouse urothelial cells. The proliferation rate of MBT-2 cells overexpressing dominant-negative TRPV2 was significantly increased. In contrast, treatment with TRPV2 activators significantly decreased the proliferation rate. TRPM7-overexpressing MBT-2 cells proliferated more slowly, as compared to mock-transfected cells. Moreover, expression of dominant-negative TRPV2 significantly decreased plasma membrane Ca²⁺ permeability of MBT-2 cells as compared to that in mock-transfected cells. Increases in the expression of TRPV2 mRNA, immunoreactivity, and TRPV2 activator-induced intracellular Ca²⁺ were also observed in T24 human bladder cancer cells. These results suggested that TRPV2 and TRPM7 were functionally expressed in bladder cancer cells and served as negative regulators of bladder cancer cell proliferation, most likely to prevent excess mechanical stresses.     

Involvement of thermosensitive TRP channels in energy metabolism

To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.     

TRP channels entering the structural era

Transient receptor potential (TRP) channels are important in many neuronal and non-neuronal physiological processes. The past 2 years have seen much progress in the use of structural biology techniques to elucidate molecular mechanisms of TRP channel gating and regulation. Two approaches have proven fruitful: (i) a divide-and-conquer strategy has provided high-resolution structural details of TRP channel fragments although it fails to explain how these fragments are integrated in the full channel; and (ii) electron microscopy of entire TRP channels has yielded low-resolution images that provide a basis for testable models of TRP channel architecture. The results of each approach, summarized in this review, provide a preview of what the future holds in TRP channel structural biology.     

Regulation of TRP channels by PIP2

Transient receptor potential (TRP) channels are regulated by a wide variety of physical and chemical factors. Recently, several members of the TRP channel family were reported to be regulated by phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂, PIP₂). This review will summarize the current knowledge on PIP₂ regulation of TRP channels and discuss the possibility that PIP₂ is a common regulator of mammalian TRP channels.     

TRP channels as sensors of oxygen availability

An ability to adapt to changes in oxygen availability is essential for survival in both prokaryotic and eukaryotic organisms. Recently, cation channels encoded by the transient receptor potential (trp) gene superfamily have been recognized as multimodal sensors of a wide variety of factors inside the cells and in the extracellular environment and also as transducers of electrical and chemical signals mediated by ions such as Ca²⁺. The functional features of TRP channels enable the body to react and adapt to different forms of environmental changes, including oxygen levels. A subclass of TRP channels regulates various cellular processes in response to fluctuations in oxygen. In this article, we describe the physiological and pathological significance of the oxygen-sensitive TRP channels, which are heterogeneous in the cellular responses to acute changes in oxygen, by contrasting their oxygen monitoring function with that of other ion channels, transporters, and enzymes. We also discuss the physiological relevance of oxygen-sensitive TRP channels as a novel class of target proteins for pharmaceutical therapeutics.     

TRP channels and traffic-related environmental pollution-induced pulmonary disease

Environmental pollutant exposures are major risk factors for adverse health outcomes, with increased morbidity and mortality in humans. Diesel exhaust (DE) is one of the major harmful components of traffic-related air pollution. Exposure to DE affects several physiological systems, including the airways, and pulmonary diseases are increased in highly populated urban areas. Hence, there are urgent needs to (1) create newer and lesser polluting fuels, (2) improve exhaust aftertreatments and reduce emissions, and (3) understand mechanisms of actions for toxic effects of both conventional and cleaner diesel fuels on the lungs. These steps could aid the development of diagnostics and interventions to prevent the negative impact of traffic-related air pollution on the pulmonary system. Exhaust from conventional, and to a lesser extent, clean fuels, contains particulate matter (PM) and more than 400 additional chemical constituents. The major toxic constituents are nitrogen oxides (NOx) and polycyclic aromatic hydrocarbons (PAHs). PM and PAHs could potentially act via transient receptor potential (TRP) channels. In this review, we will first discuss the associations between DE from conventional as well as clean fuel technologies and acute and chronic airway inflammation. We will then review possible activation and/or potentiation of TRP vanilloid type 1 (TRPV1) and ankyrin 1 (TRPA1) channels by PM and PAHs. Finally, we will discuss and summarize recent findings on the mechanisms whereby TRPs could control the link between DE and airway inflammation, which is a primary determinant leading to pulmonary disease.     

酸敏感离子通道对海马神经元树突发育的影响

目的 探讨酸敏感离子通道（ASICs）在海马神经元树突发育中的作用。方法 在体外培养第5天的原代海马神经元中转染定位于膜上的绿色荧光蛋白（F-GFP）,随后在神经元培养液中加入ASICs拮抗剂Amiloride和ASIC1a 选择性拮抗剂Psalmotoxin 1（PcTX1）抑制ASICs的功能,观察体外培养8d和14d这两个时间点海马神经元的树突生长、分支复杂程度。结果Amiloride（10-5mol/L）和PcTX1（1∶20 000稀释）处理3d对海马神经元树突分支总长度、树突分支总数均无显著影响,表明在海马神经元发育早期短时间抑制ASICs功能不影响树突发育。Amiloride（10-5mol/L）处理9d可以显著降低树突分支总长度和树突分支总数; PcTX1（1∶20 000稀释）处理9d也可以显著降低树突分支总长度,但对树突分支总数无显著影响。实验结果表明,长时间抑制ASICs功能会影响树突发育。结论 ASICs参与调节树突的发育。     

Function and regulation of TRP family channels in C. elegans

Seventeen transient receptor potential (TRP) family proteins are encoded by the C. elegans genome, and they cover all of the seven TRP subfamilies, including TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML. Classical forward and reverse genetic screens have isolated mutant alleles in every C. elegans trp gene, and their characterizations have revealed novel functions and regulatory mechanisms of TRP channels. For example, the TRPC channels TRP-1 and TRP-2 control nicotine-dependent behavior, while TRP-3, a sperm TRPC channel, is regulated by sperm activation and required for sperm–egg interactions during fertilization. Similar to their vertebrate counterparts, C. elegans TRPs function in sensory physiology. For instance, the TRPV channels OSM-9 and OCR-2 act in chemosensation, osmosensation, and touch sensation, the TRPA member TRPA-1 regulates touch sensation, while the TRPN channel TRP-4 mediates proprioception. Some C. elegans TRPM, TRPP, and TRPML members exhibit cellular functions similar to their vertebrate homologues and have provided insights into human diseases, including polycystic kidney disease, hypomagnesemia, and mucolipidosis type IV. The availability of a complete set of trp gene mutants in conjunction with its facile genetics makes C. elegans a powerful model for studying the function and regulation of TRP family channels in vivo.