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1.
Cell ; 182(3): 609-624.e21, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32640190

RESUMO

Gastrointestinal enterochromaffin cells regulate bone and gut homeostasis via serotonin (5-hydroxytryptamine [5-HT]) production. A recent report suggested that gut microbes regulate 5-HT levels; however, the precise underlying molecular mechanisms are unexplored. Here, we reveal that the cation channel Piezo1 in the gut acts as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse Piezo1 profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of Piezo1 increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders.


Assuntos
Osso e Ossos/metabolismo , Colo/metabolismo , Motilidade Gastrointestinal/genética , Canais Iônicos/metabolismo , RNA/metabolismo , Serotonina/biossíntese , Serotonina/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Osso e Ossos/citologia , Cálcio/metabolismo , Colite/genética , Colite/metabolismo , Colite/prevenção & controle , Colo/fisiologia , Fezes/química , Feminino , Motilidade Gastrointestinal/fisiologia , Células HEK293 , Humanos , Imuno-Histoquímica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Canais Iônicos/genética , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota/efeitos dos fármacos , Fator 88 de Diferenciação Mieloide/metabolismo , Osteoclastos/metabolismo , Pirazinas/farmacologia , RNA/farmacologia , Ribonuclease Pancreático/administração & dosagem , Serotonina/sangue , Serotonina/deficiência , Tiadiazóis/farmacologia
2.
Bioessays ; 46(7): e2400047, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38769699

RESUMO

Recent insights reveal the significant role of TRPV3 in warmth sensation. A novel finding elucidated how thermosensation is affected by TRPV3 membrane abundance that is modulated by the transmembrane protein TMEM79. TRPV3 is a warmth-sensitive ion channel predominantly expressed in epithelial cells, particularly skin keratinocytes. Multiple studies investigated the roles of TRPV3 in cutaneous physiology and pathophysiology. TRPV3 activation by innocuous warm temperatures in keratinocytes highlights its significance in temperature sensation, but whether TRPV3 directly contributes to warmth sensations in vivo remains controversial. This review explores the electrophysiological and structural properties of TRPV3 and how modulators affect its intricate regulatory mechanisms. Moreover, we discuss the multifaceted involvement of TRPV3 in skin physiology and pathology, including barrier formation, hair growth, inflammation, and itching. Finally, we examine the potential of TRPV3 as a therapeutic target for skin diseases and highlight its diverse role in maintaining skin homeostasis.


Assuntos
Homeostase , Queratinócitos , Pele , Canais de Cátion TRPV , Canais de Cátion TRPV/metabolismo , Humanos , Animais , Pele/metabolismo , Queratinócitos/metabolismo , Sensação Térmica/fisiologia , Dermatopatias/metabolismo , Dermatopatias/tratamento farmacológico
3.
Exp Dermatol ; 33(3): e15021, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38429832

RESUMO

Langerhans cells (LCs) are mainly present in the epidermis and mucosa, and have important roles during skin infection. Migration of LCs to lymph nodes is essential for antigen presentation. However, due to the difficulties in isolating and culturing human LCs, it is not fully understood how LCs move and interact with the extracellular matrix (ECM) through their adhesion molecules such as integrin, during the immune responses. In this study, we aimed to investigate LC motility, cell shape and the role of integrin under inflammatory conditions using monocyte-derived Langerhans cells (moLCs) as a model. As a result, lipopolysaccharide (LPS) stimulation increased adhesion on fibronectin coated substrate and integrin α5 expression in moLCs. Time-lapse imaging of moLCs revealed that stimulation with LPS elongated cell shape, whilst decreasing their motility. Additionally, this decrease in motility was not observed when pre-treated with a neutralising antibody targeting integrin α5. Together, our data suggested that activation of LCs decreases their motility by promoting integrin α5 expression to enhance their affinity to the fibronectin, which may contribute to their migration during inflammation.


Assuntos
Integrina alfa5 , Células de Langerhans , Humanos , Fibronectinas/metabolismo , Imunidade , Integrina alfa5/metabolismo , Integrinas/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos
4.
Adv Exp Med Biol ; 1461: 3-13, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39289270

RESUMO

Somatosensory neurons can sense external temperature by converting sensation of temperature information to neural activity via afferent input to the central nervous system. Various populations of somatosensory neurons have specialized gene expression, including expression of thermosensitive transient receptor potential (TRP) ion channels. Thermosensitive TRP channels are responsible for thermal transduction at the peripheral ends of somatosensory neurons and can sense a wide range of temperatures. Here we focus on several thermosensitive TRP channels including TRPV1, TRPV4, TRPM2, TRPM3, TRPM8, TRPC5, and TRPA1 in sensory neurons. TRPV3, TRPV4, and TRPC5 are also involved in somatosensation in nonneuronal cells and tissues. In particular, we discuss whether skin senses ambient temperatures through TRPV3 and TRPV4 activation in skin keratinocytes and the involvement of TRPM2 expressed by hypothalamic neurons in thermosensation in the brain.


Assuntos
Sensação Térmica , Canais de Potencial de Receptor Transitório , Humanos , Sensação Térmica/fisiologia , Sensação Térmica/genética , Animais , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/fisiologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Canais de Cátion TRPV/metabolismo , Canais de Cátion TRPV/genética , Pele/metabolismo , Pele/inervação , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPM/genética , Queratinócitos/metabolismo
5.
Proc Natl Acad Sci U S A ; 118(17)2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33888579

RESUMO

Microglia maintain central nervous system homeostasis by monitoring changes in their environment (resting state) and by taking protective actions to equilibrate such changes (activated state). These surveillance and protective roles both require constant movement of microglia. Interestingly, induced hypothermia can reduce microglia migration caused by ischemia, suggesting that microglia movement can be modulated by temperature. Although several ion channels and transporters are known to support microglia movement, the precise molecular mechanism that regulates temperature-dependent movement of microglia remains unclear. Some members of the transient receptor potential (TRP) channel superfamily exhibit thermosensitivity and thus are strong candidates for mediation of this phenomenon. Here, we demonstrate that mouse microglia exhibit temperature-dependent movement in vitro and in vivo that is mediated by TRPV4 channels within the physiological range of body temperature. Our findings may provide a basis for future research into the potential clinical application of temperature regulation to preserve cell function via manipulation of ion channel activity.


Assuntos
Movimento Celular/fisiologia , Microglia/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Células Cultivadas , Sistema Nervoso Central/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Canais de Cátion TRPV/fisiologia , Temperatura , Canais de Potencial de Receptor Transitório/metabolismo
6.
Proc Natl Acad Sci U S A ; 118(17)2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33893234

RESUMO

The stratum corneum (SC), the outermost epidermal layer, consists of nonviable anuclear keratinocytes, called corneocytes, which function as a protective barrier. The exact modes of cell death executed by keratinocytes of the upper stratum granulosum (SG1 cells) remain largely unknown. Here, using intravital imaging combined with intracellular Ca2+- and pH-responsive fluorescent probes, we aimed to dissect the SG1 death process in vivo. We found that SG1 cell death was preceded by prolonged (∼60 min) Ca2+ elevation and rapid induction of intracellular acidification. Once such intracellular ionic changes were initiated, they became sustained, irreversibly committing the SG1 cells to corneocyte conversion. Time-lapse imaging of isolated murine SG1 cells revealed that intracellular acidification was essential for the degradation of keratohyalin granules and nuclear DNA, phenomena specific to SC corneocyte formation. Furthermore, intravital imaging showed that the number of SG1 cells exhibiting Ca2+ elevation and the timing of intracellular acidification were both tightly regulated by the transient receptor potential cation channel V3. The functional activity of this protein was confirmed in isolated SG1 cells using whole-cell patch-clamp analysis. These findings provide a theoretical framework for improved understanding of the unique molecular mechanisms underlying keratinocyte-specific death mode, namely corneoptosis.


Assuntos
Morte Celular/fisiologia , Células Epidérmicas/metabolismo , Queratinócitos/metabolismo , Animais , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Diferenciação Celular , Epiderme/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Queratinócitos/fisiologia , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp/métodos , Pele
7.
J Biol Chem ; 298(9): 102271, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35850302

RESUMO

Animals detect heat using thermosensitive transient receptor potential (TRP) channels. In insects, these include TRP ankyrin 1 (TRPA1), which in mosquitoes is crucial for noxious heat avoidance and thus is an appealing pest control target. However, the molecular basis for heat-evoked activation has not been fully elucidated, impeding both studies of the molecular evolution of temperature sensitivity and rational design of inhibitors. In TRPA1 and other thermosensitive TRPs, the N-terminal cytoplasmic ankyrin repeat (AR) domain has been suggested to participate in heat-evoked activation, but the lack of a structure containing the full AR domain has hindered our mechanistic understanding of its role. Here, we focused on elucidating the structural basis of apparent temperature threshold determination by taking advantage of two closely related mosquito TRPA1s from Aedes aegypti and Culex pipiens pallens with 86.9% protein sequence identity but a 10 °C difference in apparent temperature threshold. We identified two positions in the N-terminal cytoplasmic AR domain of these proteins, E417 (A. aegypti)/Q414 (C. pipiens) and R459 (A. aegypti)/Q456 (C. pipiens), at which a single exchange of amino acid identity was sufficient to change apparent thresholds by 5 to 7 °C. We further found that the role of these positions is conserved in TRPA1 of a third related species, Anopheles stephensi. Our results suggest a structural basis for temperature threshold determination as well as for the evolutionary adaptation of mosquito TRPA1 to the wide range of climates inhabited by mosquitoes.


Assuntos
Aedes , Repetição de Anquirina , Culex , Temperatura Alta , Canal de Cátion TRPA1 , Aedes/genética , Aedes/fisiologia , Animais , Repetição de Anquirina/genética , Culex/genética , Culex/fisiologia , Domínios Proteicos , Canal de Cátion TRPA1/química , Canal de Cátion TRPA1/genética
8.
Mol Biol Evol ; 39(9)2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35994363

RESUMO

Environmental temperature is a critical factor for all forms of life, and thermal tolerance defines the habitats utilized by a species. Moreover, the evolutionary tuning of thermal perception can also play a key role in habitat selection. Yet, the relative importance of thermal tolerance and perception in environmental adaptation remains poorly understood. Thermal conditions experienced by anuran tadpoles differ among species due to the variation in breeding seasons and water environments selected by parental frogs. In the present study, heat tolerance and avoidance temperatures were compared in tadpoles from five anuran species that spatially and temporally inhabit different thermal niches. These two parameters were positively correlated with each other and were consistent with the thermal conditions of habitats. The species difference in avoidance temperature was 2.6 times larger than that in heat tolerance, suggesting the importance of heat avoidance responses in habitat selection. In addition, the avoidance temperature increased after warm acclimation, especially in the species frequently exposed to heat in their habitats. Characterization of the heat-sensing transient receptor potential ankyrin 1 (TRPA1) ion channel revealed an amphibian-specific alternatively spliced variant containing a single valine insertion relative to the canonical alternative spliced variant of TRPA1, and this novel variant altered the response to thermal stimuli. The two alternatively spliced variants of TRPA1 exhibited different thermal responses in a species-specific manner, which are likely to be associated with a difference in avoidance temperatures among species. Together, our findings suggest that the functional change in TRPA1 plays a crucial role in thermal adaptation processes.


Assuntos
Temperatura Alta , Resposta Táctica , Aclimatação/genética , Animais , Anquirinas , Anuros/genética , Aprendizagem da Esquiva
9.
Biochem Biophys Res Commun ; 654: 1-9, 2023 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-36871485

RESUMO

The skin is a protective interface between the internal organs and environment and functions not only as a physical barrier but also as an immune organ. However, the immune system in the skin is not fully understood. A member of the thermo-sensitive transient receptor potential (TRP) channel family, TRPM4, which acts as a regulatory receptor in immune cells, was recently reported to be expressed in human skin and keratinocytes. However, the function of TRPM4 in immune responses in keratinocytes has not been investigated. In this study, we found that treatment with BTP2, a known TRPM4 agonist, reduced cytokine production induced by tumor necrosis factor (TNF) α in normal human epidermal keratinocytes and in immortalized human epidermal keratinocytes (HaCaT cells). This cytokine-reducing effect was not observed in TRPM4-deficient HaCaT cells, indicating that TRPM4 contributed to the control of cytokine production in keratinocytes. Furthermore, we identified aluminum potassium sulfate, as a new TRPM4 activating agent. Aluminum potassium sulfate reduced Ca2+ influx by store-operated Ca2+ entry in human TRPM4-expressing HEK293T cells. We further confirmed that aluminum potassium sulfate evoked TRPM4-mediated currents, showing direct evidence for TRPM4 activation. Moreover, treatment with aluminum potassium sulfate reduced cytokine expression induced by TNFα in HaCaT cells. Taken together, our data suggested that TRPM4 may serve as a new target for the treatment of skin inflammatory reactions by suppressing the cytokine production in keratinocytes, and aluminum potassium sulfate is a useful ingredient to prevent undesirable skin inflammation through TRPM4 activation.


Assuntos
Dermatite , Canais de Cátion TRPM , Humanos , Células HEK293 , Queratinócitos/metabolismo , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Imunidade , Canais de Cátion TRPM/metabolismo
10.
Biol Pharm Bull ; 46(7): 939-945, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37394645

RESUMO

Transient receptor potential (TRP) channels play a significant role in taste perception. TRP ankyrin 1 (TRPA1) is present in the afferent sensory neurons and is activated by food-derived ingredients, such as Japanese horseradish, cinnamon, and garlic. The present study aimed to investigate the expression of TRPA1 in taste buds, and determine its functional roles in taste perception using TRPA1-deficient mice. In circumvallate papillae, TRPA1 immunoreactivity colocalised with P2X2 receptor-positive taste nerves but not with type II or III taste cell markers. Behavioural studies showed that TRPA1 deficiency significantly reduced sensitivity to sweet and umami tastes, but not to salty, bitter, and sour tastes, compared to that in wild-type animals. Furthermore, administration of the TRPA1 antagonist HC030031 significantly decreased taste preference to sucrose solution compared to that in the vehicle-treated group in the two-bottle preference tests. TRPA1 deficiency did not affect the structure of circumvallate papillae or the expression of type II or III taste cell and taste nerve markers. Adenosine 5'-O-(3-thio)triphosphate evoked inward currents did not differ between P2X2- and P2X2/TRPA1-expressing human embryonic kidney 293T cells. TRPA1-deficient mice had significantly decreased c-fos expression in the nucleus of the solitary tract in the brain stem following sucrose stimulation than wild-type mice. Taken together, the current study suggested that TRPA1 in the taste nerve contributes to the sense of sweet taste in mice.


Assuntos
Papilas Gustativas , Percepção Gustatória , Camundongos , Humanos , Animais , Paladar/fisiologia , Anquirinas/metabolismo , Papilas Gustativas/metabolismo , Sacarose
11.
J Physiol ; 600(19): 4287-4302, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36042566

RESUMO

The transient receptor potential melastatin type 2 (TRPM2) channel is a non-selective cation channel that has high Ca2+ permeability. TRPM2 is sensitive to warm temperatures and is expressed in cells and tissues that are maintained at core body temperature. TRPM2 activity is also regulated by endogenous factors including redox signalling, cytosolic Ca2+ and adenosine diphosphate ribose. As a result of its wide expression and function at core body temperature, these endogenous factors could regulate TRPM2 activity at body temperature under physiological and pathophysiological conditions. We previously reported that cellular redox signalling can lower TRPM2 temperature thresholds, although the mechanism that regulates these thresholds is unclear. Here, we used biochemical and electrophysiological techniques to explore another regulatory mechanism for TRPM2 temperature thresholds that is mediated by TRPM2 phosphorylation. Our results show that: (1) the temperature threshold for TRPM2 activation is lowered by cytosolic Ca2+ ; (2) protein kinase C-mediated phosphorylation of TRPM2 counteracts the effect of cytosolic Ca2+ ; and (3) Thr738 in mouse TRPM2 that lies near the Ca2+ binding site in the cytosolic cleft of the transmembrane domain is a potential phosphorylation site that may be involved in phosphorylation-mediated elevation of TRPM2 thresholds. These findings provide structure-based evidence to understand how temperature thresholds of thermo-sensitive TRP channels (thermo-TRPs) are determined and regulated. KEY POINTS: The transient receptor potential melastatin type 2 (TRPM2) ion channel is temperature-sensitive and Ca2+ -permeable. Endogenous factors and pathways such as redox signalling can regulate TRPM2 activity at body temperature under physiological and pathophysiological conditions. In the present study, we report the novel finding that cytosolic Ca2+ lowers the temperature threshold for TRPM2 activation in a concentration-dependent manner. Protein kinase C-mediated phosphorylation of TRPM2 at amino acid Thr782 elevates the temperature threshold for activation by counteracting the effects of cytosolic Ca2+ . These findings provide structure-based evidence to understand how temperature thresholds of thermo-sensitive TRP channels are determined and regulated.


Assuntos
Canais de Cátion TRPM , Adenosina Difosfato Ribose/metabolismo , Aminoácidos/metabolismo , Animais , Cálcio/metabolismo , Cátions/metabolismo , Camundongos , Fosforilação , Proteína Quinase C/metabolismo , Canais de Cátion TRPM/metabolismo , Temperatura
12.
FASEB J ; 35(4): e21238, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33715198

RESUMO

5,6-dihydroxy-8Z,11Z,14Z,17Z-eicosatetraenoic acid (5,6-DiHETE) is an eicosapentaenoic acid-derived lipid metabolite, which we previously detected in inflamed mouse colon. In this study, we investigated the pathophysiological roles of 5,6-DiHETE in murine colitis and its underlying mechanisms of action, focusing on the effects on transient receptor potential vanilloid (TRPV) channel activity. Oral administration of dextran sodium sulfate (DSS, 2%, for 4 days) caused colon inflammation, which peaked on day 7 and gradually declined by day 18. 5,6-DiHETE concentration in colon tissue was significantly increased during the healing phase of colitis (days 9 to 18). In vitro study showed that pretreatment with 5,6-DiHETE (0.1-1 µM, 30 minutes) significantly inhibited endothelial barrier disruption induced by a TRPV4 agonist (GSK1016790A, 50 nM). Intracellular Ca2+ imaging also showed that pretreatment with 5,6-DiHETE (1 µM, 10 minutes) reduced GSK1016790A-induced intracellular Ca2+ increase in HEK293T cells overexpressing TRPV4. In vivo, intraperitoneal administration of 5,6-DiHETE (50 µg kg-1  day-1 ) during the healing phase accelerated the recovery from DSS-induced colitis. Pathological studies showed that the administration of 5,6-DiHETE inhibited edema formation and leukocyte infiltration in inflamed colon tissue. In conclusion, we identified 5,6-DiHETE as a novel endogenous TRPV4 antagonist, and we also demonstrated that its administration promotes the healing of colitis by inhibiting inflammatory responses.


Assuntos
Ácidos Araquidônicos/farmacologia , Colite/induzido quimicamente , Regulação da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Canais de Cátion TRPV/metabolismo , Animais , Colite/tratamento farmacológico , Sulfato de Dextrana/toxicidade , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Canais de Cátion TRPV/genética
13.
Proc Natl Acad Sci U S A ; 116(48): 24359-24365, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31719194

RESUMO

Thermosensitive transient receptor potential (TRP) ion channels detect changes in ambient temperature to regulate body temperature and temperature-dependent cellular activity. Rodent orthologs of TRP vanilloid 2 (TRPV2) are activated by nonphysiological heat exceeding 50 °C, and human TRPV2 is heat-insensitive. TRPV2 is required for phagocytic activity of macrophages which are rarely exposed to excessive heat, but what activates TRPV2 in vivo remains elusive. Here we describe the molecular mechanism of an oxidation-induced temperature-dependent gating of TRPV2. While high concentrations of H2O2 induce a modest sensitization of heat-induced inward currents, the oxidant chloramine-T (ChT), ultraviolet A light, and photosensitizing agents producing reactive oxygen species (ROS) activate and sensitize TRPV2. This oxidation-induced activation also occurs in excised inside-out membrane patches, indicating a direct effect on TRPV2. The reducing agent dithiothreitol (DTT) in combination with methionine sulfoxide reductase partially reverses ChT-induced sensitization, and the substitution of the methionine (M) residues M528 and M607 to isoleucine almost abolishes oxidation-induced gating of rat TRPV2. Mass spectrometry on purified rat TRPV2 protein confirms oxidation of these residues. Finally, macrophages generate TRPV2-like heat-induced inward currents upon oxidation and exhibit reduced phagocytosis when exposed to the TRP channel inhibitor ruthenium red (RR) or to DTT. In summary, our data reveal a methionine-dependent redox sensitivity of TRPV2 which may be an important endogenous mechanism for regulation of TRPV2 activity and account for its pivotal role for phagocytosis in macrophages.


Assuntos
Metionina/metabolismo , Canais de Cátion TRPV/química , Canais de Cátion TRPV/metabolismo , Canais de Cálcio/química , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Cloraminas/química , Escherichia coli/genética , Temperatura Alta , Humanos , Peróxido de Hidrogênio/química , Macrófagos , Metionina/química , Mutação , Oxidantes/química , Oxirredução , Técnicas de Patch-Clamp , Fagocitose , Canais de Cátion TRPM/química , Canais de Cátion TRPM/metabolismo , Canais de Cátion TRPV/genética , Compostos de Tosil/química
14.
Int J Mol Sci ; 23(9)2022 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-35562940

RESUMO

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel that is broadly expressed in different human tissues, including the digestive system, where it acts as a molecular sensor and a transducer that regulates a variety of functional activities. Despite the extensive research to determine the role of this channel in the physiology and pathophysiology of different organs, the unique morphological and functional features of TRPV4 in the esophagus remain largely unknown. Ten years ago, TRPV4 was shown to be highly expressed in esophageal epithelial cells where its activation induces Ca2+-dependent ATP release, which, in turn, mediates several functions, ranging from mechanosensation to wound healing. This review summarizes the research progress on TRPV4, and focuses on the functional expression of TRPV4 in esophageal epithelium and its possible role in different esophageal diseases that would support TRPV4 as a candidate target for future therapeutic approaches to treat patients with these conditions.


Assuntos
Esôfago , Canais de Cátion TRPV , Células Epiteliais/metabolismo , Mucosa Esofágica/metabolismo , Esôfago/metabolismo , Humanos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
15.
Am J Hum Genet ; 102(6): 1104-1114, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861107

RESUMO

Transient neonatal hyperparathyroidism (TNHP) is etiologically a heterogeneous condition. One of the etiologies is an insufficient maternal-fetal calcium transport through the placenta. We report six subjects with homozygous and/or compound-heterozygous mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6), an epithelial Ca2+-selective channel associated with this condition. Exome sequencing on two neonates with skeletal findings consistent with neonatal hyperparathyroidism identified homozygous frameshift mutations before the first transmembrane domain in a subject born to first-cousins parents of Pakistani descent as well as compound-heterozygous mutations (a combination of a frameshift mutation and an intronic mutation that alters mRNA splicing) in an individual born to a non-consanguineous couple of African descent. Subsequently, targeted mutation analysis of TRPV6 performed on four other individuals (born to non-consanguineous Japanese parents) with similar X-rays findings identified compound-heterozygous mutations. The skeletal findings improved or resolved in most subjects during the first few months of life. We identified three missense variants (at the outer edges of the second and third transmembrane domains) that alter the localization of the TRPV6: one recurrent variant at the S2-S3 loop and two recurrent variants (in the fourth ankyrin repeat domain) that impair TRPV6 stability. Compound heterozygous loss-of-function mutations for the pathogenic frameshift allele and the allele with an intronic c.607+5G>A mutation resulted in the most severe phenotype. These results suggest that TNHP is an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport.


Assuntos
Canais de Cálcio/genética , Cálcio/metabolismo , Feto/metabolismo , Hiperparatireoidismo/genética , Troca Materno-Fetal , Mutação/genética , Placenta/metabolismo , Canais de Cátion TRPV/genética , Adulto , Sequência de Bases , Feminino , Células HEK293 , Humanos , Hiperparatireoidismo/sangue , Hiperparatireoidismo/diagnóstico por imagem , Recém-Nascido , Transporte de Íons , Masculino , Linhagem , Gravidez
16.
Biol Pharm Bull ; 44(7): 947-957, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34193690

RESUMO

Transient receptor potential melastatin 8 (TRPM8) is a non-selective cation channel activated by mild cooling and chemical agents including menthol. Nonsteroidal anti-inflammatory drugs have antipyretic, analgesic effects, and they can cause stomach and small intestinal injury. The current study investigated the role of TRPM8 in the pathogenesis of indomethacin-induced small intestinal injury. In male TRPM8-deficient (TRPM8KO) and wild-type (WT) mice, intestinal injury was induced via the subcutaneous administration of indomethacin. In addition, the effect of WS-12, a specific TRPM8 agonist, was examined in TRPM8KO and WT mice with indomethacin-induced intestinal injury. TRPM8KO mice had a significantly higher intestinal ulcerogenic response to indomethacin than WT mice. The repeated administration of WS-12 significantly attenuated the severity of intestinal injury in WT mice. However, this response was abrogated in TRPM8KO mice. Furthermore, in TRPM8-enhanced green fluorescent protein (EGFP) transgenic mice, which express EGFP under the direction of TRPM8 promoter, the EGFP signals in the indomethacin-treated intestinal mucosa were upregulated. Further, the EGFP signals were commonly found in calcitonin gene-related peptide (CGRP)-positive sensory afferent neurons and partly colocalized with substance P (SP)-positive neurons in the small intestine. The intestinal CGRP-positive neurons were significantly upregulated after the administration of indomethacin in WT mice. Nevertheless, this response was abrogated in TRPM8KO mice. In contrast, indomethacin increased the expression of intestinal SP-positive neurons in not only WT mice but also TRPM8KO mice. Thus, TRPM8 has a protective effect against indomethacin-induced small intestinal injury. This response may be mediated by the upregulation of CGRP, rather than SP.


Assuntos
Anti-Inflamatórios não Esteroides , Indometacina , Canais de Cátion TRPM/genética , Anilidas/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/lesões , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Masculino , Mentol/análogos & derivados , Mentol/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/metabolismo , Substância P/metabolismo , Canais de Cátion TRPM/agonistas , Canais de Cátion TRPM/metabolismo
17.
Biosci Biotechnol Biochem ; 85(11): 2295-2299, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34468713

RESUMO

Human susceptibility to NaCl varies depending on temperature and pH, the molecular mechanisms of which remain unclear. The voltage-dependent chloride channel, transmembrane channel-like 4 (TMC4), is activated at approximately 40 °C and is suppressed at pH 5.5. As these are similar in character to human sensory evaluations, human TMC4 may be involved in human salt taste reception.


Assuntos
Temperatura
18.
Lab Invest ; 100(2): 274-284, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31641226

RESUMO

Physiological brain temperature is an important determinant of brain function, and it is well established that changes in brain temperature dynamically influence hippocampal neuronal activity. We previously demonstrated that the thermosensor TRPV4 is activated at physiological brain temperature in hippocampal neurons thereby controlling neuronal excitability in vitro. Here, we examined whether TRPV4 regulates neuronal excitability through its activation by brain temperature in vivo. We locally cooled the hippocampus using our novel electrical device and demonstrated constitutive TRPV4 activation in normal mouse brain. We generated a model of partial epilepsy by utilizing kindling stimuli in the ventral hippocampus of wild type (WT) or TRPV4-deficient (TRPV4KO) mice and obtained electroencephalograms (EEG). The frequencies of epileptic EEG in WT mice were significantly larger than those in TRPV4KO mice. These results indicate that TRPV4 activation is involved in disease progression of epilepsy. We expected that disease progression would enhance hyperexcitability and lead to hyperthermia in the epileptogenic foci. To confirm this hypothesis, we developed a new device to measure exact brain temperature only in a restricted local area. From the recording results by the new device, we found that the brain temperatures in epileptogenic zones were dramatically elevated compared with normal regions. Furthermore, we demonstrated that the temperature elevation was critical for disease progression. Based on these results, we speculate that brain cooling treatment at epileptogenic foci would effectively suppress epileptic discharges through inhibition of TRPV4. Notably, the cooling treatment drastically suppressed neuronal discharges dependent on the inactivation of TRPV4.


Assuntos
Temperatura Corporal/fisiologia , Epilepsia , Febre , Canais de Cátion TRPV , Animais , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Febre/metabolismo , Febre/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
19.
Digestion ; 101(1): 6-11, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31770754

RESUMO

BACKGROUND: Transient receptor potential vanilloid 4 (TRPV4) is activated by stretch (mechanical), warm temperature, some epoxyeicosatrienoic acids, and lipopolysaccharide. TRPV4 is expressed throughout the gastrointestinal epithelia and its activation induces adenosine triphosphate (ATP) exocytosis that is involved in visceral hypersensitivity. As an ATP transporter, vesicular nucleotide transporter (VNUT) mediates ATP storage in secretory vesicles and ATP release via exocytosis upon stimulation. SUMMARY: TRPV4 is sensitized under inflammatory conditions by a variety of factors, including proteases and serotonin, whereas methylation-dependent silencing of TRPV4 expression is associated with various pathophysiological conditions. Gastrointestinal epithelia also release ATP in response to hypo-osmolality or acid through molecular mechanisms that remain unclear. These synergistically released ATP could be involved in visceral hypersensitivity. Low concentrations of the first generation bisphosphate, clodronate, were recently reported to inhibit VNUT activity and thus clodronate may be a safe and potent therapeutic option to treat visceral pain. Key Messages: This review focuses on: (1) ATP and TRPV4 activities in gastrointestinal epithelia; (2) factors that could modulate TRPV4 activity in gastrointestinal epithelia; and (3) the inhibition of VNUT as a potential novel therapeutic strategy for functional gastrointestinal disorders.


Assuntos
Trifosfato de Adenosina/metabolismo , Trato Gastrointestinal/metabolismo , Proteínas de Transporte de Nucleotídeos/metabolismo , Canais de Cátion TRPV/metabolismo , Dor Abdominal/tratamento farmacológico , Dor Abdominal/etiologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Animais , Doença Crônica , Ácido Clodrônico/farmacologia , Ácido Clodrônico/uso terapêutico , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Mucosa/efeitos dos fármacos , Mucosa/metabolismo , Mucosa/fisiopatologia , Proteínas de Transporte de Nucleotídeos/antagonistas & inibidores , Pressorreceptores/efeitos dos fármacos , Pressorreceptores/metabolismo , Pressorreceptores/fisiopatologia , Receptores Purinérgicos P2/efeitos dos fármacos , Receptores Purinérgicos P2/metabolismo
20.
Lab Invest ; 99(2): 210-230, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30413814

RESUMO

In order to understand the pathobiology of neurotrophic keratopathy, we established a mouse model by coagulating the first branch of the trigeminal nerve (V1 nerve). In our model, the sensory nerve in the central cornea disappeared and remaining fibers were sparse in the peripheral limbal region. Impaired corneal epithelial healing in the mouse model was associated with suppression of both cell proliferation and expression of stem cell markers in peripheral/limbal epithelium as well as a reduction of transient receptor potential vanilloid 4 (TRPV4) expression in tissue. TRPV4 gene knockout also suppressed epithelial repair in mouse cornea, although it did not seem to directly modulate migration of epithelium. In a co-culture experiment, TRPV4-introduced KO trigeminal ganglion upregulated nerve growth factor (NGF) in cultured corneal epithelial cells, but ganglion with a control vector did not. TRPV4 gene introduction into a damaged V1 nerve rescues the impairment of epithelial healing in association with partial recovery of the stem/progenitor cell markers and upregulation of cell proliferation and of NGF expression in the peripheral/limbal epithelium. Gene transfer of TRPV4 did not accelerate the regeneration of nerve fibers. Sensory nerve TRPV4 is critical to maintain stemness of peripheral/limbal basal cells, and is one of the major mechanisms of homeostasis maintenance of corneal epithelium.


Assuntos
Epitélio Corneano , Células-Tronco , Canais de Cátion TRPV/metabolismo , Nervo Trigêmeo/metabolismo , Cicatrização/fisiologia , Animais , Células Cultivadas , Epitélio Corneano/citologia , Epitélio Corneano/lesões , Epitélio Corneano/metabolismo , Técnicas de Inativação de Genes , Camundongos , Células-Tronco/citologia , Células-Tronco/metabolismo , Canais de Cátion TRPV/genética , Nervo Trigêmeo/química
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