Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Med ; 20(10): 1187-92, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25216637

RESUMO

The integrity of the plasma membrane is maintained through an active repair process, especially in skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness. An important cause of these group of diseases is defective repair of sarcolemmal injuries, which normally requires Ca(2+) sensor proteins and Ca(2+)-dependent delivery of intracellular vesicles to the sites of injury. MCOLN1 (also known as TRPML1, ML1) is an endosomal and lysosomal Ca(2+) channel whose human mutations cause mucolipidosis IV (ML4), a neurodegenerative disease with motor disabilities. Here we report that ML1-null mice develop a primary, early-onset MD independent of neural degeneration. Although the dystrophin-glycoprotein complex and the known membrane repair proteins are expressed normally, membrane resealing was defective in ML1-null muscle fibers and also upon acute and pharmacological inhibition of ML1 channel activity or vesicular Ca(2+) release. Injury facilitated the trafficking and exocytosis of vesicles by upmodulating ML1 channel activity. In the dystrophic mdx mouse model, overexpression of ML1 decreased muscle pathology. Collectively, our data have identified an intracellular Ca(2+) channel that regulates membrane repair in skeletal muscle via Ca(2+)-dependent vesicle exocytosis.


Assuntos
Distrofia Muscular Animal/metabolismo , Sarcolema/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Canais de Cálcio/deficiência , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Membrana Celular/metabolismo , Exocitose , Feminino , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos mdx , Camundongos Knockout , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/patologia , Sarcolema/patologia , Canais de Potencial de Receptor Transitório/deficiência , Canais de Potencial de Receptor Transitório/genética
2.
Dev Cell ; 26(5): 511-24, 2013 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-23993788

RESUMO

Phagocytosis of large extracellular particles such as apoptotic bodies requires delivery of the intracellular endosomal and lysosomal membranes to form plasmalemmal pseudopods. Here, we identified mucolipin TRP channel 1 (TRPML1) as the key lysosomal Ca2+ channel regulating focal exocytosis and phagosome biogenesis. Both particle ingestion and lysosomal exocytosis are inhibited by synthetic TRPML1 blockers and are defective in macrophages isolated from TRPML1 knockout mice. Furthermore, TRPML1 overexpression and TRPML1 agonists facilitate both lysosomal exocytosis and particle uptake. Using time-lapse confocal imaging and direct patch clamping of phagosomal membranes, we found that particle binding induces lysosomal PI(3,5)P2 elevation to trigger TRPML1-mediated lysosomal Ca2+ release specifically at the site of uptake, rapidly delivering TRPML1-resident lysosomal membranes to nascent phagosomes via lysosomal exocytosis. Thus phagocytic ingestion of large particles activates a phosphoinositide- and Ca2+-dependent exocytosis pathway to provide membranes necessary for pseudopod extension, leading to clearance of senescent and apoptotic cells in vivo.


Assuntos
Lisossomos/genética , Fagocitose/genética , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismo , Envelhecimento/genética , Animais , Cálcio/metabolismo , Exocitose/genética , Regulação da Expressão Gênica , Camundongos , Tamanho da Partícula , Fosfatos de Fosfatidilinositol/metabolismo , Canais de Potencial de Receptor Transitório/agonistas , Canais de Potencial de Receptor Transitório/antagonistas & inibidores
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...