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1.
Curr Top Dev Biol ; 150: 91-128, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35817507

RESUMO

Wnts are a family of secreted, lipid-modified signaling glycoproteins that regulate a multiplicity of fundamental biological processes. Wnt signaling is essential for embryonic development, controlling body axis patterning, cell proliferation, cell migration and cell fate specification needed for proper tissue and organ formation. In adulthood, Wnt signaling controls tissue regeneration in a wide range of organs, and disturbance of this system is common in cancer and other diseases. A key feature of Wnt signaling is that it is a local process. Wnts signal via paracrine, cell-to-cell communication. Upon synthesis and transport to the plasma membrane in the "sending" cell, Wnts travel to nearby "receiving" cells. At the plasma membrane of these receiving cells, they interact with a variety of cell-surface receptors. This interaction triggers a diversity of different downstream signaling events, including the stabilization of ß-catenin and tissue-specific changes in gene expression. Wnt signaling is a local event because as an indispensable step in their maturation, Wnts are palmitoleated immediately after synthesis. This lipid modification is essential for Wnts to be transported and biologically active, but it also renders them highly hydrophobic. This makes all Wnts highly dependent on carrier proteins and specialized cellular structures both for intra- and inter-cellular movement. How this complex machinery acts in concert to deliver its highly important payload from the place of synthesis to the correct site of delivery is under active investigation. Here, we review the current understanding of how lipid-modified Wnts are processed, transported, and guided to their place of action.


Assuntos
Proteínas Wnt , Via de Sinalização Wnt , Padronização Corporal/genética , Movimento Celular , Lipídeos , Proteínas Wnt/metabolismo , Via de Sinalização Wnt/fisiologia
2.
Proc Natl Acad Sci U S A ; 116(10): 4706-4715, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30770447

RESUMO

Zn2+, Mg2+, and Ca2+ are essential minerals required for a plethora of metabolic processes and signaling pathways. Different categories of cation-selective channels and transporters are therefore required to tightly control the cellular levels of individual metals in a cell-specific manner. However, the mechanisms responsible for the organismal balance of these essential minerals are poorly understood. Herein, we identify a central and indispensable role of the channel-kinase TRPM7 for organismal mineral homeostasis. The function of TRPM7 was assessed by single-channel analysis of TRPM7, phenotyping of TRPM7-deficient cells in conjunction with metabolic profiling of mice carrying kidney- and intestine-restricted null mutations in Trpm7 and animals with a global "kinase-dead" point mutation in the gene. The TRPM7 channel reconstituted in lipid bilayers displayed a similar permeability to Zn2+ and Mg2+ Consistently, we found that endogenous TRPM7 regulates the total content of Zn2+ and Mg2+ in cultured cells. Unexpectedly, genetic inactivation of intestinal rather than kidney TRPM7 caused profound deficiencies specifically of Zn2+, Mg2+, and Ca2+ at the organismal level, a scenario incompatible with early postnatal growth and survival. In contrast, global ablation of TRPM7 kinase activity did not affect mineral homeostasis, reinforcing the importance of the channel activity of TRPM7. Finally, dietary Zn2+ and Mg2+ fortifications significantly extended the survival of offspring lacking intestinal TRPM7. Hence, the organismal balance of divalent cations critically relies on one common gatekeeper, the intestinal TRPM7 channel.


Assuntos
Mucosa Intestinal/metabolismo , Minerais/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Cálcio/metabolismo , Técnicas de Inativação de Genes , Homeostase , Rim/metabolismo , Magnésio/metabolismo , Camundongos , Camundongos Knockout , Canais de Cátion TRPM/genética , Zinco/metabolismo
3.
Cell Calcium ; 76: 129-131, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30470536

RESUMO

TRPM7 is an atypical type of ion channel because its pore-forming moiety is covalently linked to a protein kinase domain. The channel-kinase TRPM7 controls a wide range of biological processes such as mineral homeostasis, immune responses, cell motility, proliferation and differentiation. Earlier this year, Duan J & co-workers [1] published three TRPM7 structures resolved by cryo-electron microscopy (cryo-EM). This study tremendously advances our mechanistic understanding of TRPM7 channel function and forms the basis for informed structure-function assessment of this extraordinary protein.


Assuntos
Canais de Cátion TRPM , Animais , Cálcio , Microscopia Crioeletrônica , Homeostase , Humanos , Magnésio , Proteínas Serina-Treonina Quinases
4.
Pharmacol Ther ; 184: 159-176, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29129644

RESUMO

Transient receptor potential (TRP) proteins TRPM6 and TRPM7 are α-kinase-coupled divalent cation-selective channels activated upon a reduction of cytosolic levels of Mg2+ and Mg·ATP. Emerging evidence indicate that one of the main physiological functions of TRPM6 and TRPM7 is maintaining of cellular metabolism of Mg2+ and likely other essential metals such as Ca2+ and Zn2+. Recent experiments with genetic animal models have shown that TRPM6 and TRPM7 are essential for epithelial Mg2+ transport in the placenta and intestine. In addition, mutations in TRPM6 or TRPM7 have been linked to Mg2+ deficiency in humans. However, many key functional aspects of these remarkable proteins as well as mechanisms of the associated channelopathies remain incompletely understood. The present review article highlights the recent significant progress in the field with the focus on the vital roles of TRPM7 and TRPM7 in mineral homeostasis.


Assuntos
Homeostase/fisiologia , Proteínas Quinases/metabolismo , Canais de Potencial de Receptor Transitório/fisiologia , Animais , Humanos , Magnésio/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Canais de Cátion TRPM/fisiologia
5.
Elife ; 52016 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-27991852

RESUMO

Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.


Assuntos
Desenvolvimento Embrionário , Mucosa Intestinal/enzimologia , Mucosa Intestinal/metabolismo , Magnésio/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Feminino , Técnicas de Inativação de Genes , Camundongos , Placenta/enzimologia , Placenta/metabolismo , Gravidez , Análise de Sobrevida , Canais de Cátion TRPM/genética , Saco Vitelino/enzimologia , Saco Vitelino/metabolismo
6.
J Gen Physiol ; 147(6): 467-83, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27185858

RESUMO

Within the ion channel-coupled purine receptor (P2X) family, P2X7 has gained particular interest because of its role in immune responses and in the growth control of several malignancies. Typical hallmarks of P2X7 are nonselective and noninactivating cation currents that are elicited by high concentrations (0.1-10 mM) of extracellular ATP. Here, we observe spurious ATP-induced currents in HEK293 cells that neither express P2X7 nor display ATP-induced Ca(2+) influx or Yo-Pro-1 uptake. Although the biophysical properties of these ionic currents resemble those of P2X7 in terms of their reversal potential close to 0 mV, nonrectifying current-voltage relationship, current run-up during repeated ATP application, and augmentation in bath solutions containing low divalent cation (DIC) concentrations, they are poorly inhibited by established P2X7 antagonists. Because high ATP concentrations reduce the availability of DICs, these findings prompted us to ask whether other channel entities may become activated by our experimental regimen. Indeed, a bath solution with no added DICs yields similar currents and also a rapidly inactivating Na(+)-selective conductance. We provide evidence that TRPM7 and ASIC1a (acid-sensing ion channel type Ia)-like channels account for these noninactivating and phasic current components, respectively. Furthermore, we find ATP-induced currents in rat C6 glioma cells, which lack functional P2X receptors but express TRPM7. Thus, the observation of an atypical P2X7-like conductance may be caused by the activation of TRPM7 by ATP, which scavenges free DICs and thereby releases TRPM7 from permeation block. Because TRPM7 has a critical role in controlling the intracellular Mg(2+) homeostasis and regulating tumor growth, these data imply that the proposed role of P2X7 in C6 glioma cell proliferation deserves reevaluation.


Assuntos
Potenciais de Ação , Trifosfato de Adenosina/metabolismo , Glioma/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Canais de Cátion TRPM/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Células HEK293 , Humanos , Magnésio/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Ratos
7.
Nat Commun ; 7: 11097, 2016 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-27020697

RESUMO

Mg(2+) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg(2+)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7(fl/fl-Pf4Cre)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7(fl/fl-Pf4Cre) MKs, which is rescued by Mg(2+) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.


Assuntos
Citoesqueleto/metabolismo , Homeostase , Magnésio/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Trombopoese , Animais , Plaquetas/metabolismo , Humanos , Megacariócitos/metabolismo , Camundongos , Proteínas Mutantes/metabolismo , Miosina não Muscular Tipo IIA/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Canais de Cátion TRPM/deficiência , Trombocitopenia/metabolismo , Trombocitopenia/patologia
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