Stimulation of transient receptor potential vanilloid 4 channel suppresses abnormal activation of microglia induced by lipopolysaccharide.
Glia
; 60(5): 761-70, 2012 May.
Article
en En
| MEDLINE
| ID: mdl-22331560
Microglia are intrinsic immune cells in the brain. In response to neurodegenerative events, excessively activated microglia change their shapes and release various cytokines leading to the pathogenesis of central nervous system (CNS) disease. Because the intracellular mechanisms of this process are still unclear, we have evaluated the functional roles of transient receptor potential vanilloid 4 (TRPV4) channel expressed in the microglia. Robust microglial activation after an injection of lipopolysaccharide (LPS) into the mouse cerebral ventricle was suppressed by concurrent administration of a selective TRPV4 agonist, 4α-phorbol 12,13-didecanoate (4α-PDD). When the mechanism was further investigated using cultured rat microglia intrinsically expressing functional TRPV4, release of tumor necrosis factor-α (TNF-α) and expression of galectin-3 were both increased by LPS. These increases were significantly suppressed by cotreatment with 4α-PDD, and the inhibitory effects of 4α-PDD were abolished by knockdown of TRPV4 or TRPV4 antagonists. The amplitude of voltage-dependent K(+) current, which is augmented during microglial activation, was also suppressed by 4α-PDD treatment. Opening of TRPV4 channels with 4α-PDD induced membrane depolarization mainly by increasing Na(+) influx. In addition, mimicking depolarization with a high-K(+) solution suppressed LPS-induced TNF-α release and galectin-3 upregulation. Both depolarizing treatments with 4α-PDD and high-K(+) solution decreased store-operated Ca(2+) influx caused by thapsigargin. These results suggest that depolarization in response to opening of the TRPV4 channel attenuates the driving force for extracellular Ca(2+) and suppresses microglial activation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Regulación hacia Abajo
/
Regulación hacia Arriba
/
Lipopolisacáridos
/
Microglía
/
Canales Catiónicos TRPV
Límite:
Animals
Idioma:
En
Revista:
Glia
Asunto de la revista:
NEUROLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Japón
Pais de publicación:
Estados Unidos