The TRP channels, a remarkably functional family

TRP cation channels display an extraordinary assortment of selectivities and activation mechanisms, some of which represent previously unrecognized modes for regulating ion channels. Moreover, the biological roles of TRP channels appear to be equally diverse and range from roles in pain perception to male aggression.     

Transient receptor potential, TRP channels: a new family of channels broadly expressed

Transient receptor potential, TRP channels are a new superfamily of functionally versatile non-selective cation channels present from yeast to mammals. On the basis of their structural homology, TRP channels are subdivided in 7 groups : TRPC 1-7 Canonical, TRPV 1-6 Vanilloid, TRPM 1-8 Melastatin, TRPP 1-3 Polycystin, TRPML Mucolipin, TRPA Ankyrin and TRPN (NO mechanotransducer potential C), the latter not expressed in mammals. Their cloning and heterologous expression allowed to demonstrating that these channels are generally weakly voltage-dependent. They are activated by various ligands involving a signal transduction cascade as well as directly by multiple compounds, heat and pH. TRP channels are found in a broad range of cell types. TRP channels are essential in allowing animals to sense the outside world and cells to sense their local environment. Following mutations or anomalous behaviour, these channels have a major role in several human diseases.     

TRP channels: an overview

The TRP ("transient receptor potential") family of ion channels now comprises more than 30 cation channels, most of which are permeable for Ca2+, and some also for Mg2+. On the basis of sequence homology, the TRP family can be divided in seven main subfamilies: the TRPC ('Canonical') family, the TRPV ('Vanilloid') family, the TRPM ('Melastatin') family, the TRPP ('Polycystin') family, the TRPML ('Mucolipin') family, the TRPA ('Ankyrin') family, and the TRPN ('NOMPC') family. The cloning and characterization of members of this cation channel family has exploded during recent years, leading to a plethora of data on the roles of TRPs in a variety of tissues and species, including mammals, insects, and yeast. The present review summarizes the most pertinent recent evidence regarding the structural and functional properties of TRP channels, focusing on the regulation and physiology of mammalian TRPs.     

The venerable inveterate invertebrate TRP channels

The transient receptor potential (TRP) superfamily is subdivided into four main classes of cation channels, TRPC, TRPV, TRPM and TRPN, each of which includes members in worms, flies, mice and humans. While the biophysical features of many of the mammalian channels have been described, relatively little is known concerning the biological roles of these channels. Forward genetic screens in Drosophila melanogaster and Caenorhabditis elegans have led to the identification of the founding members of each of these four subfamilies. Moreover, phenotypic analyses of invertebrate mutants have contributed greatly to our understanding of the roles of TRP proteins. A recurring theme is that many of these proteins function in sensory signaling processes ranging from vision to olfaction, osmosensation, light touch, social feeding, and temperature- and mechanically-induced nociception. In addition, at least one invertebrate TRP protein is required for cell division. As many of these functions may be conserved among the mammalian TRPs, the invertebrate TRPs offer valuable genetic handles for characterizing the functions of these cation channels in vivo.     

The TRP ion channel family

Mammalian homologues of the Drosophila transient receptor potential (TRP) channel gene encode a family of at least 20 ion channel proteins. They are widely distributed in mammalian tissues, but their specific physiological functions are largely unknown. A common theme that links the TRP channels is their activation or modulation by phosphatidylinositol signal transduction pathways. The channel subunits have six transmembrane domains that most probably assemble into tetramers to form non-selective cationic channels, which allow for the influx of calcium ions into cells. Three subgroups comprise the TRP channel family; the best understood of these mediates responses to painful stimuli. Other proposed functions include repletion of intracellular calcium stores, receptor-mediated excitation and modulation of the cell cycle.     

Modulation of temperature-sensitive TRP channels

Animals sense temperature--either cold or hot--by the direct activation of temperature-sensitive members of the TRP family of ion channels, the thermo-TRPs. To date, six TRP channels--TRPV1-4, TRPM8 and TRPA1--have been reported to be directly activated by heat and to be involved in thermosensation. Temperature sensing can be modulated by phosphorylation of intracellular residues by protein kinases or by insertion of new channels into the cell membrane. In this review we provide a brief overview of the properties of thermo-TRPs, and we summarise signalling pathways involved in their regulation.     

X-ray crystallography of TRP channels

Transient receptor potential (TRP) ion channels are molecular sensors of a large variety of stimuli including temperature, mechanical stress, voltage, small molecules including capsaicin and menthol, and lipids such as phosphatidylinositol 4,5-bisphosphate (PIP₂). Since the same TRP channels may respond to different physical and chemical stimuli, they can serve as signal integrators. Many TRP channels are calcium permeable and contribute to Ca²⁺ homeostasis and signaling. Although the TRP channel family was discovered decades ago, only recently have the structures of many of these channels been solved, largely by cryo-electron microscopy (cryo-EM). Complimentary to cryo-EM, X-ray crystallography provides unique tools to unambiguously identify specific atoms and can be used to study ion binding in channel pores. In this review we describe crystallographic studies of the TRP channel TRPV6. The methodology used in these studies may serve as a template for future structural analyses of different types of TRP and other ion channels.     

Intracellular trafficking of TRP channels

Thirteen years ago, it was suggested that exocytotic insertion of store-operated channels into the plasma membrane lead to increased Ca(2+) entry in non-excitable cells upon G protein-coupled or tyrosine kinase receptor stimulation. Since the discovery of the TRP channel superfamily and their involvement in receptor-induced Ca(2+) entry, many studies have shown that different members of the TRP superfamily translocate into the plasma membrane upon stimulation. While the exact molecular mechanism by which TRP channels insert into the plasma membrane is unknown, TRP-binding proteins have been shown to directly regulate this trafficking. This review summarizes recent advances related to the mechanism of TRP channel trafficking, focusing on the role of TRP-binding proteins.     

温度感受相关的TRP蛋白家族研究进展

机体通过感受器接受各种环境刺激,经感觉神经将信息传到大脑皮层感觉区,产生相应的感觉。然而,机体内的中枢或末梢感受器是如何感受各种刺激的还所知甚少。近年来对瞬时感受器电位(transient receptor potential,TRP)蛋白家族的研究提供了探索关于温度感知机构的新线索,对揭开感觉机构的生物学机制具有重要而深远的意义。本文主要以与温度感受相关的TRP蛋白质家族为中心,阐述其结构及生物学特性。     

Regulation of TRP channels by phosphorylation

The transient receptor potential (TRP) channels are a group of Ca2+-permeable cation channels (except TRPM4 and TRPM5) that function as cellular sensors of various internal and external stimuli. Most of these channels are expressed in the nervous system and they play a key role in sensory physiology. They may respond to temperature, pressure, inflammatory agents, pain, osmolarity, taste and many other stimuli. Recent development indicates that the activity of these channels is regulated by protein phosphorylation and dephosphorylation of serine, threonine, and tyrosine residues. In this review, we present a comprehensive summary of the literature regarding the TRP channel regulation by different protein kinases.     

TRP channels: targets for the relief of pain

Patients with inflammatory or neuropathic pain experience hypersensitivity to mechanical, thermal and/or chemical stimuli. Given the diverse etiologies and molecular mechanisms of these pain syndromes, an approach to developing successful therapies may be to target ion channels that contribute to the detection of thermal, mechanical and chemical stimuli and promote the sensitization and activation of nociceptors. Transient Receptor Potential (TRP) channels have emerged as a family of evolutionarily conserved ligand-gated ion channels that contribute to the detection of physical stimuli. Six TRPs (TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1) have been shown to be expressed in primary afferent nociceptors, pain sensing neurons, where they act as transducers for thermal, chemical and mechanical stimuli. This short review focuses on their contribution to pain hypersensitivity associated with peripheral inflammatory and neuropathic pain states.     

When a TRP goes bad: Transient receptor potential channels in addiction

Drug addiction is a psychiatric disease state, wherein a drug is impulsively and compulsively self-administered despite negative consequences. This repeated administration results in permanent changes to nervous system physiology and architecture. The molecular pathways affected by addictive drugs are complex and inter-dependent on each other. Recently, various new proteins and protein families have been discovered to play a role in drug abuse. Emerging players in this phenomenon include TRP (Transient Receptor Potential) family channels, which are primarily known to function in sensory systems. Several TRP family channels identified in both vertebrates and invertebrates are involved in psychostimulant-induced plasticity, suggesting their involvement in drug dependence. This review summarizes various observations, both from studies in humans and other organisms, which support a role for these channels in the development of drug-related behaviors.     

TRP channels in Drosophila photoreceptors: the lipid connection

The light-sensitive current in Drosophila photoreceptors is mediated by transient receptor potential (TRP) channels, at least two members of which (TRP and TRPL) are activated downstream of phospholipase C (PLC) in response to light. Recent evidence is reviewed suggesting that Drosophila TRP channels are activated by one or more lipid products of PLC activity: namely diacylglycerol (DAG), its metabolites (polyunsaturated fatty acids) or the reduction in phosphatidylinositol 4,5-bisphosphate (PIP(2)). The most compelling evidence for this view comes from analysis of rdgA mutants which are unable to effectively metabolise DAG due to a defect in DAG kinase. The rdgA mutation leads to constitutive activation of both TRP and TRPL channels and dramatically increases sensitivity to light in hypomorphic mutations of PLC and G protein.     

Regulation of TRP channels by N-linked glycosylation

A subset of TRP channel proteins undergoes regulatory N-linked glycosylation. A glycosylation site in the first extracellular loop of TRPV5 is enzymatically cleaved by a secreted glucuronidase, indirectly regulating channel function. Members of the TRPC family share a similar site, although details about a regulatory role are lacking. A second conserved TRP channel glycosylation site is found immediately adjacent to the channel pore-forming loop; both TRPV1 and TRPV4--and perhaps other TRPV family members--are influenced by glycosylation at this site. N-linked glycosylation, and the dynamic regulation of this process, substantially impacts function and targeting of TRP channels.