RESUMO
The perception of nociceptive signals, which are translated into pain, plays a fundamental role in the survival of organisms. Because pain is linked to a negative sensation, animals learn to avoid noxious signals. These signals are detected by receptors, which include some members of the transient receptor potential (TRP) family of ion channels that act as transducers of exogenous and endogenous noxious cues. These proteins have been in the focus of the field of physiology for several years, and much knowledge of how they regulate the function of the cell types and organs where they are expressed has been acquired. The last decade has been especially exciting because the 'resolution revolution' has allowed us to learn the molecular intimacies of TRP channels using cryogenic electron microscopy. These findings, in combination with functional studies, have provided insights into the role played by these channels in the generation and maintenance of pain.
Assuntos
Canais de Potencial de Receptor Transitório , Animais , Dor , Sensação/fisiologia , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
The ability to detect stimuli from the environment plays a pivotal role in our survival. The molecules that allow the detection of such signals include ion channels, which are proteins expressed in different cells and organs. Among these ion channels, the transient receptor potential (TRP) family responds to the presence of diverse chemicals, temperature, and osmotic changes, among others. This family of ion channels includes the TRPV or vanilloid subfamily whose members serve several physiological functions. Although these proteins have been studied intensively for the last two decades, owing to their structural and functional complexities, a number of controversies regarding their function still remain. Here, we discuss some salient features of their regulation in light of these controversies and outline some of the efforts pushing the field forward.
Assuntos
Canais Iônicos , Canais de Potencial de Receptor Transitório , Humanos , Canais de Potencial de Receptor Transitório/química , Canais de Potencial de Receptor Transitório/metabolismoRESUMO
The Transient Receptor Potential Vanilloid 4 (TRPV4) channel has been shown to function in many physiological and pathophysiological processes. Despite abundant information on its importance in physiology, very few endogenous agonists for this channel have been described, and very few underlying mechanisms for its activation have been clarified. TRPV4 is expressed by several types of cells, such as vascular endothelial, and skin and lung epithelial cells, where it plays pivotal roles in their function. In the present study, we show that TRPV4 is activated by lysophosphatidic acid (LPA) in both endogenous and heterologous expression systems, pinpointing this molecule as one of the few known endogenous agonists for TRPV4. Importantly, LPA is a bioactive glycerophospholipid, relevant in several physiological conditions, including inflammation and vascular function, where TRPV4 has also been found to be essential. Here we also provide mechanistic details of the activation of TRPV4 by LPA and another glycerophospholipid, lysophosphatidylcholine (LPC), and show that LPA directly interacts with both the N- and C-terminal regions of TRPV4 to activate this channel. Moreover, we show that LPC activates TRPV4 by producing an open state with a different single-channel conductance to that observed with LPA. Our data suggest that the activation of TRPV4 can be finely tuned in response to different endogenous lipids, highlighting this phenomenon as a regulator of cell and organismal physiology. KEY POINTS: The Transient Receptor Potential Vaniloid (TRPV) 4 ion channel is a widely distributed protein with important roles in normal and disease physiology for which few endogenous ligands are known. TRPV4 is activated by a bioactive lipid, lysophosphatidic acid (LPA) 18:1, in a dose-dependent manner, in both a primary and a heterologous expression system. Activation of TRPV4 by LPA18:1 requires residues in the N- and C-termini of the ion channel. Single-channel recordings show that TRPV4 is activated with a decreased current amplitude (conductance) in the presence of lysophosphatidylcholine (LPC) 18:1, while LPA18:1 and GSK101 activate the channel with a larger single-channel amplitude. Distinct single-channel amplitudes produced by LPA18:1 and LPC18:1 could differentially modulate the responses of the cells expressing TRPV4 under different physiological conditions.
Assuntos
Canais de Potencial de Receptor Transitório , Canais de Cátion TRPV/metabolismo , Lisofosfatidilcolinas/farmacologia , Lisofosfolipídeos/farmacologiaRESUMO
Transient receptor potential (TRP) ion channels are proteins that are expressed by diverse tissues and that play pivotal functions in physiology. These channels are polymodal and are activated by several stimuli. Among TRPs, some members of this family of channels respond to changes in ambient temperature and are known as thermoTRPs. These proteins respond to heat or cold in the noxious range and some of them to temperatures considered innocuous, as well as to mechanical, osmotic, and/or chemical stimuli. In addition to this already complex ability to respond to different signals, the activity of these ion channels can be fine-tuned by lipids. Two lipids well known to modulate ion channel activity are phosphatidylinositol 4,5-bisphosphate (PIP2) and cholesterol. These lipids can either influence the function of these proteins through direct interaction by binding to a site in the structure of the ion channel or through indirect mechanisms, which can include modifying membrane properties, such as curvature and rigidity, by regulating their expression or by modulating the actions of other molecules or signaling pathways that affect the physiology of ion channels. Here, we summarize the key aspects of the regulation of thermoTRP channels by PIP2 and cholesterol.
Assuntos
Canais de Potencial de Receptor Transitório , Canais de Potencial de Receptor Transitório/metabolismo , Temperatura , Temperatura Baixa , Fosfatidilinositóis , Colesterol/metabolismoRESUMO
BACKGROUND & AIMS: Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of antipruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus. METHODS: Pruritogenicity of lysophosphatidylcholine (LPC), LPA's precursor, was examined in naïve mice, cholestatic mice, and nonhuman primates. LPC's pruritogenicity involving keratinocyte TRPV4 was studied using genetic and pharmacologic approaches, cultured keratinocytes, ion channel physiology, and structural computational modeling. Activation of pruriceptor sensory neurons by microRNA-146a (miR-146a), secreted from keratinocytes, was identified by in vitro and ex vivo Ca2+ imaging assays. Sera from patients with primary biliary cholangitis were used for measuring the levels of LPC and miR-146a. RESULTS: LPC was robustly pruritic in mice. TRPV4 in skin keratinocytes was essential for LPC-induced itch and itch in mice with cholestasis. Three-dimensional structural modeling, site-directed mutagenesis, and channel function analysis suggested a TRPV4 C-terminal motif for LPC binding and channel activation. In keratinocytes, TRPV4 activation by LPC induced extracellular release of miR-146a, which activated TRPV1+ sensory neurons to cause itch. LPC and miR-146a levels were both elevated in sera of patients with primary biliary cholangitis with itch and correlated with itch intensity. Moreover, LPC and miR-146a were also increased in sera of cholestatic mice and elicited itch in nonhuman primates. CONCLUSIONS: We identified LPC as a novel cholestatic pruritogen that induces itch through epithelia-sensory neuron cross talk, whereby it directly activates skin keratinocyte TRPV4, which rapidly releases miR-146a to activate skin-innervating TRPV1+ pruriceptor sensory neurons. Our findings support the new concept of the skin, as a sensory organ, playing a critical role in cholestatic itch, beyond liver, peripheral sensory neurons, and central neural pathways supporting pruriception.
Assuntos
Colestase/complicações , Queratinócitos/metabolismo , Lisofosfatidilcolinas , Prurido/metabolismo , Células Receptoras Sensoriais/metabolismo , Pele/inervação , Canais de Cátion TRPV/metabolismo , Adulto , Idoso , Animais , Comportamento Animal , Células Cultivadas , Colestase/genética , Colestase/metabolismo , Colestase/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Prurido/induzido quimicamente , Prurido/genética , Prurido/fisiopatologia , Transdução de Sinais , Canais de Cátion TRPV/genéticaRESUMO
TRPV4 is a nonselective cationic channel responsive to several physical and chemical stimuli. Defects in TRPV4 channel function result in human diseases, such as skeletal dysplasias, arthropathies, and peripheral neuropathies. Nonetheless, little is known about the role of TRPV4 in other cellular functions, such as nuclear Ca2+ homeostasis or Ca2+ -regulated transcription. Here, we confirmed the presence of the full-length TRPV4 channel in the nuclei of nonpolarized Madin-Darby canine kidney cells. Confocal Ca2+ imaging showed that activation of the channel increases cytoplasmic and nuclear Ca2+ leading to translocation of TRPV4 out of the nucleus together with ß-catenin, a transcriptional regulator in the Wnt signaling pathway fundamental in embryogenesis, organogenesis, and cellular homeostasis. TRPV4 inhibits ß-catenin transcriptional activity through a direct interaction dependent upon channel activity. This interaction also occurs in undifferentiated osteoblastoma and neuroblastoma cell models. Our results suggest a mechanism in which TRPV4 may regulate differentiation in several cellular contexts.
Assuntos
Cálcio/metabolismo , Núcleo Celular/metabolismo , Células Epiteliais/metabolismo , Rim/citologia , Modelos Biológicos , Canais de Cátion TRPV/metabolismo , Transcrição Gênica , beta Catenina/genética , Animais , Sinalização do Cálcio , Diferenciação Celular , Linhagem Celular Tumoral , Cães , Humanos , Ativação do Canal Iônico , Células Madin Darby de Rim Canino , Neuroblastoma/patologia , Osteossarcoma/patologia , Ligação Proteica , Domínios Proteicos , Transporte Proteico , Canais de Cátion TRPV/química , beta Catenina/metabolismoRESUMO
The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.
Assuntos
Dor/metabolismo , Receptores sigma/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Capsaicina/metabolismo , Linhagem Celular , Membrana Celular/genética , Membrana Celular/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/genética , Progesterona/metabolismo , Ligação Proteica , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/genética , Receptor Sigma-1RESUMO
The TRPV1 cation nonselective ion channel plays an essential role in thermosensation and perception of other noxious stimuli. TRPV1 can be activated by low extracellular pH, high temperature, or naturally occurring pungent molecules such as allicin, capsaicin, or resiniferatoxin. Its noxious thermal sensitivity makes it an important participant as a thermal sensor in mammals. However, details of the mechanism of channel activation by increases in temperature remain unclear. Here, we used a combination of approaches to try to understand the role of the ankyrin repeat domain (ARD) in channel behavior. First, a computational modeling approach by coarse-grained molecular dynamics simulation of the whole TRPV1 embedded in a phosphatidylcholine and phosphatidylethanolamine membrane provides insight into the dynamics of this channel domain. Global analysis of the structural ensemble shows that the ARD is a region that sustains high fluctuations during dynamics at different temperatures. We then performed biochemical and thermal stability studies of the purified ARD by the means of circular dichroism and tryptophan fluorescence and demonstrate that this region undergoes structural changes at similar temperatures that lead to TRPV1 activation. Our data suggest that the ARD is a dynamic module and that it may participate in controlling the temperature sensitivity of TRPV1.
Assuntos
Repetição de Anquirina , Canais de Cátion TRPV , Animais , Capsaicina , Temperatura Alta , Humanos , Simulação de Dinâmica Molecular , Canais de Cátion TRPV/metabolismoRESUMO
The Transient Receptor Potential Vanilloid 1 (TRPV1) channel is a polymodal protein with functions widely linked to the generation of pain. Several agonists of exogenous and endogenous nature have been described for this ion channel. Nonetheless, detailed mechanisms and description of binding sites have been resolved only for a few endogenous agonists. This review focuses on summarizing discoveries made in this particular field of study and highlighting the fact that studying the molecular details of activation of the channel by different agonists can shed light on biophysical traits that had not been previously demonstrated.
Assuntos
Ativação do Canal Iônico , Domínios Proteicos , Canais de Cátion TRPV/química , Canais de Cátion TRPV/metabolismo , Animais , Sítios de Ligação/genética , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Canais de Cátion TRPV/genéticaRESUMO
The Transient Receptor Vanilloid 1 (TRPV1) or capsaicin receptor is a nonselective cation channel, which is abundantly expressed in nociceptors. This channel is an important transducer of several noxious stimuli, having a pivotal role in pain development. Several TRPV1 studies have focused on understanding its structure and function, as well as on the identification of compounds that regulate its activity. The intracellular roles of these channels have also been explored, highlighting TRPV1's actions in the homeostasis of Ca2+ in organelles such as the mitochondria. These studies have evidenced how the activation of TRPV1 affects mitochondrial functions and how this organelle can regulate TRPV1-mediated nociception. The close relationship between this channel and mitochondria has been determined in neuronal and non-neuronal cells, demonstrating that TRPV1 activation strongly impacts on cell physiology. This review focuses on describing experimental evidence showing that TRPV1 influences mitochondrial function.
Assuntos
Sinalização do Cálcio/genética , Mitocôndrias/genética , Dor/genética , Canais de Cátion TRPV/genética , Animais , Cálcio/metabolismo , Humanos , Mitocôndrias/metabolismo , Nociceptividade/fisiologia , Dor/fisiopatologia , Transdução de Sinais/genéticaRESUMO
Transient receptor potential (TRP) channels are remarkable transmembrane protein complexes that are essential for the physiology of the tissues in which they are expressed. They function as non-selective cation channels allowing for the signal transduction of several chemical, physical and thermal stimuli and modifying cell function. These channels play pivotal roles in the nervous and reproductive systems, kidney, pancreas, lung, bone, intestine, among others. TRP channels are finely modulated by different mechanisms: regulation of their function and/or by control of their expression or cellular/subcellular localization. These mechanisms are subject to being affected by several endogenously-produced compounds, some of which are of a lipidic nature such as steroids. Fascinatingly, steroids and TRP channels closely interplay to modulate several physiological events. Certain TRP channels are affected by the typical genomic long-term effects of steroids but others are also targets for non-genomic actions of some steroids that act as direct ligands of these receptors, as will be reviewed here.
Assuntos
Androgênios/metabolismo , Estrogênios/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Humanos , Canais de Potencial de Receptor Transitório/química , Canais de Potencial de Receptor Transitório/genéticaRESUMO
Transient Receptor Potential (TRP) channels are a family of ion channels whose members are distributed among all kinds of animals, from invertebrates to vertebrates. The importance of these molecules is exemplified by the variety of physiological roles they play. Perhaps, the most extensively studied member of this family is the TRPV1 ion channel; nonetheless, the activity of TRPV4 has been associated to several physio and pathophysiological processes, and its dysfunction can lead to severe consequences. Several lines of evidence derived from animal models and even clinical trials in humans highlight TRPV4 as a therapeutic target and as a protein that will receive even more attention in the near future, as will be reviewed here.
Assuntos
Canais de Cátion TRPV/fisiologia , Animais , Cálcio/metabolismo , Bovinos , Endotélio Vascular/metabolismo , Humanos , Rim/metabolismo , Camundongos , Microcirculação , Dor/metabolismo , Permeabilidade , Prognóstico , Domínios Proteicos , Ratos , Vasos Retinianos , Pele/metabolismoRESUMO
Cholesterol is the one of the major constituents of cell membranes providing these structures with a certain degree of rigidity. Proteins, such as ion channels, are molecules inserted in cell membranes and their activity is regulated by cholesterol and other molecules of a lipidic nature present in them. The molecular mechanisms underlying the regulation of ion channels by lipids and similar molecules have been an object of study for several years. A little over two decades ago, the first mammalian member of the Transient Receptor Potential (TRP) family of ion channels was cloned. This protein, the TRPV1 channel, was shown to integrate several types of noxious signals in sensory neurons and to participate in processes associated to the generation of pain. Thus, TRPV1 has become the target of intense research directed towards finding potential inhibitors of its activity in an effort to control pain. To date, several activators and positive modulators of the activity of TRPV1 have been described. However, very few naturally-occurring inhibitors are known. An endogenously-produced molecule that inhibits the activity of TRPV1 is cholesterol. This chapter focuses on describing the mechanisms by which the activity of TRPV1 can be regulated by this sterol.
Assuntos
Colesterol/química , Dor , Canais de Cátion TRPV/química , Animais , Lipídeos , Neurônios AferentesRESUMO
Lysophosphatidic acid (LPA) is a bioactive phospholipid that exhibits a wide array of functions that include regulation of protein synthesis and adequate development of organisms. LPA is present in the membranes of cells and in the serum of several mammals and has also been shown to participate importantly in pathophysiological conditions. For several decades it was known that LPA produces some of its effects in cells through its interaction with specific G protein-coupled receptors, which in turn are responsible for signaling pathways that regulate cellular function. Among the target proteins for LPA receptors are ion channels that modulate diverse aspects of the physiology of cells and organs where they are expressed. However, recent studies have begun to unveil direct effects of LPA on ion channels, highlighting this phospholipid as a direct agonist and adding to the knowledge of the field of lipid-protein interactions. Moreover, the roles of LPA in pathophysiological conditions associated with the function of some ion channels have also begun to be clarified, and molecular mechanisms have been identified. This review focuses on the effects of LPA on ion channel function under normal and pathological conditions and highlights our present knowledge of the mechanisms by which it regulates the function and expression of N- and T-type Ca++ channels; M-type K+ channel and inward rectifier K+ channel subunit 2.1; transient receptor potential (TRP) melastatin 2, TRP vanilloid 1, and TRP ankyrin 1 channels; and TWIK-related K+ channel 1 (TREK-1), TREK-2, TWIK-related spinal cord K+ channel (TRESK), and TWIK-related arachidonic acid-stimulated K+ channel (TRAAK).
Assuntos
Canais Iônicos/metabolismo , Lisofosfolipídeos/metabolismo , Dor/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Convulsões/metabolismo , Animais , Humanos , Lisofosfolipídeos/química , Receptores Acoplados a Proteínas G/metabolismo , Transdução de SinaisRESUMO
The transient receptor potential (TRP) family of ion channels is constituted by several nonselective cation channels that are activated by diverse stimuli and that function as polymodal receptors. TRP ion channels are expressed in neural and nonneural tissues where they play important roles in cell physiology. The activation of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by some natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity. Other compounds that regulate TRP ion channel function are some endogenously synthetized lipid compounds. One such example of a compound of lipidic nature, commonly found in cells, is cholesterol. Cholesterol has been shown to exert positive and negative roles on TRP ion channel activity, albeit through different mechanisms which include a direct interaction of this molecule with specific amino acids located in the sequence of these channels or through the recruitment of the channels into specialized membrane microdomains (lipid rafts or caveolae). In this chapter, we will discuss important aspects of cholesterol as a regulator of some members of the TRP family of ion channels, and we will highlight the role of cholesterol on thermo-, chemo-, and osmosensation through regulation of the activity of these proteins.
Assuntos
Colesterol/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Humanos , Canais de Potencial de Receptor Transitório/químicaRESUMO
The transient receptor potential vanilloid 1 (TRPV1) ion channel is a polymodal protein that responds to various stimuli, including capsaicin (the pungent compound found in chili peppers), extracellular acid, and basic intracellular pH, temperatures close to 42 °C, and several lipids. Lysophosphatidic acid (LPA), an endogenous lipid widely associated with neuropathic pain, is an agonist of the TRPV1 channel found in primary afferent nociceptors and is activated by other noxious stimuli. Agonists or antagonists of lipid and other chemical natures are known to possess specific structural requirements for producing functional effects on their targets. To better understand how LPA and other lipid analogs might interact and affect the function of TRPV1, we set out to determine the structural features of these lipids that result in the activation of TRPV1. By changing the acyl chain length, saturation, and headgroup of these LPA analogs, we established strict requirements for activation of TRPV1. Among the natural LPA analogs, we found that only LPA 18:1, alkylglycerophosphate 18:1, and cyclic phosphatidic acid 18:1, all with a monounsaturated C18 hydrocarbon chain activate TRPV1, whereas polyunsaturated and saturated analogs do not. Thus, TRPV1 shows a more restricted ligand specificity compared with LPA G-protein-coupled receptors. We synthesized fatty alcohol phosphates and thiophosphates and found that many of them with a single double bond in position Δ9, 10, or 11 and Δ9 cyclopropyl group can activate TRPV1 with efficacy similar to capsaicin. Finally, we developed a pharmacophore and proposed a mechanistic model for how these lipids could induce a conformational change that activates TRPV1.
Assuntos
Lisofosfolipídeos/metabolismo , Canais de Cátion TRPV/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Conformação Proteica , Canais de Cátion TRPV/químicaRESUMO
The transient receptor potential vanilloid 1 ion channel is responsible for the perception of high temperatures and low extracellular pH, and it is also involved in the response to some pungent compounds. Importantly, it is also associated with the perception of pain and noxious stimuli. Here, we attempt to discern the molecular organization and location of the N and C termini of the transient receptor potential vanilloid 1 ion channel by measuring FRET between genetically attached enhanced yellow and cyan fluorescent protein to the N or C terminus of the channel protein, expressed in transfected HEK 293 cells or Xenopus laevis oocytes. The static measurements of the domain organization were mapped into an available cryo-electron microscopy density of the channel with good agreement. These measurements also provide novel insights into the organization of terminal domains and their proximity to the plasma membrane.
Assuntos
Membrana Celular/fisiologia , Transferência Ressonante de Energia de Fluorescência/métodos , Ativação do Canal Iônico/fisiologia , Canais de Cátion TRPV/metabolismo , Algoritmos , Animais , Membrana Celular/química , Membrana Celular/ultraestrutura , Microscopia Crioeletrônica , Feminino , Células HEK293 , Humanos , Cinética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Potenciais da Membrana/fisiologia , Modelos Moleculares , Oócitos/metabolismo , Oócitos/fisiologia , Técnicas de Patch-Clamp , Multimerização Proteica , Estrutura Terciária de Proteína , Ratos , Canais de Cátion TRPV/química , Canais de Cátion TRPV/genética , Xenopus laevisRESUMO
Transient receptor potential channels have been put forward as regulators of insulin secretion. A role for the TRPV1 ion channel in insulin secretion has been suggested in pancreatic beta cell lines. We explored whether TRPV1 is functionally expressed in RINm5F and primary beta cells from neonate and adult rats. We examined if capsaicin could activate cationic non-selective currents. Our results show that TRPV1 channels are not functional in insulin-secreting cells, since capsaicin did not produce current activation, not even under culture conditions known to induce the expression of other ion channels in these cells. Although TRPV1 channels seem to be irrelevant for the physiology of isolated beta cells, they may play a role in glucose homeostasis acting through the nerve fibers that regulate islet function. At the physiological level, we observed that Trpv1 (-/-) mice presented lower fasting insulin levels than their wild-type littermates, however, we did not find differences between these experimental groups nor in the glucose tolerance test or in the insulin secretion. However, we did find that the Trpv1 (-/-) mice exhibited a higher insulin sensitivity compared to their wild-type counterparts. Our results demonstrate that TRPV1 does not contribute to glucose-induced insulin secretion in beta cells as was previously thought, but it is possible that it may control insulin sensitivity.
Assuntos
Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Células Cultivadas , Secreção de Insulina , Camundongos , Ratos , Canais de Cátion TRPV/genéticaRESUMO
There is a subgroup of transient receptor potential (TRP) ion channels that are responsive to temperature (thermo-TRP channels). These are important to a variety of sensory and physiological phenomena such as pain and taste perception. All thermo-TRP channels known to date are subject to modulation by lipidic molecules of many kinds, from the ubiquitous cholesterol to more specialized molecules such as prostaglandins. Although the mechanisms and sites of binding of lipids on thermo-TRPs are largely unknown, the explosion on research of lipids and ion channels has revealed previously unsuspected roles for them. Diacyl glycerol is a lipid produced by phospholipase C (PLC) and it was discovered to modulate TRP channels in the eye of the fly, and many mammal TRP channels have been found to interact with lipids. While most of the lipids acting on thermo-TRP channels have been found to activate them, there are a few capable of inhibition. Phosphatidylinositol 4,5-bisphosphate is even capable of both inhibition and activation on a couple of thermo-TRPs, depending on the cellular context. More data is required to assess the mechanism through which lipids affect thermo-TRP channel activity and the physiological importance of this interaction.
Assuntos
Metabolismo dos Lipídeos , Sensação Térmica , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Canais de Potencial de Receptor Transitório/químicaRESUMO
The members of the superfamily of Transient Receptor Potential (TRP) ion channels are physiologically important molecules that have been studied for many years and are still being intensively researched. Among the vanilloid TRP subfamily, the TRPV4 ion channel is an interesting protein due to its involvement in several essential physiological processes and in the development of various diseases. As in other proteins, changes in its function that lead to the development of pathological states, have been closely associated with modification of its regulation by different molecules, but also by the appearance of mutations which affect the structure and gating of the channel. In the last few years, some structures for the TRPV4 channel have been solved. Due to the importance of this protein in physiology, here we discuss the recent progress in determining the structure of the TRPV4 channel, which has been achieved in three species of animals (Xenopus tropicalis, Mus musculus, and Homo sapiens), highlighting conserved features as well as key differences among them and emphasizing the binding sites for some ligands that play crucial roles in its regulation.