RESUMEN
The transition metal copper (Cu) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and potentially damaging to the cell. Free Cu is virtually absent in the cell. The descriptions of the structural and functional organization of the metallothioneins, Cu-chaperones and P-type ATPases as well as of the mechanisms that regulate their distribution and functioning in the cell have enormously advanced our understanding of the Cu homeostasis and metabolism in the last decade. Cu is stored by metallothioneins and distributed by specialized chaperones to specific cell targets that make use of its redox properties. Transfer of Cu to newly synthesized cuproenzymes and Cu disposal is performed by the individual or concerted actions of the P-type ATPases ATP7A and ATP7B expressed in tissues. In mammalians liver is the major captor, distributor and excreter of Cu. Mutations in the P-type ATPases that interfere with their functioning and traffic are cause of the life-threatening Wilson (ATP7B) and Menkes (ATP7A) diseases.
Asunto(s)
Cobre/metabolismo , Adenosina Trifosfatasas/deficiencia , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Animales , Proteínas de Transporte de Catión/deficiencia , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Cobre/administración & dosificación , Cobre/deficiencia , Cobre/farmacocinética , ATPasas Transportadoras de Cobre , Dieta , Complejo IV de Transporte de Electrones/metabolismo , Glutatión/metabolismo , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/metabolismo , Homeostasis , Humanos , Hígado/metabolismo , Síndrome del Pelo Ensortijado/genética , Síndrome del Pelo Ensortijado/metabolismo , Metalotioneína/metabolismo , Modelos Biológicos , Chaperonas Moleculares/metabolismo , Mutación , Oxidación-Reducción , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1RESUMEN
Here, we report that Cdk5 activation is stimulated by insulin and plays a key role in the regulation of GLUT4-mediated glucose uptake in 3T3-L1 adipocytes. Insulin activation of Cdk5 requires PI3K signaling. Insulin-activated Cdk5 phosphorylates E-Syt1, a 5 C2-domain protein-related to the synaptotagmins that is induced during adipocyte differentiation. Phosphorylated E-Syt1 associates with GLUT4, an event inhibited by the Cdks inhibitor roscovitine. Cdk5 silencing inhibits glucose uptake by 3T3-L1 adipocytes. These studies elucidate a previously unknown activity of Cdk5 and demonstrate the involvement of this kinase in the regulation of insulin-dependent glucose uptake in adipocytes.
Asunto(s)
Adipocitos/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Glucosa/metabolismo , Insulina/fisiología , Proteínas de la Membrana/metabolismo , Células 3T3-L1 , Adipocitos/citología , Animales , Transporte Biológico , Proteínas de Unión al Calcio , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , FosforilaciónRESUMEN
Glucose entry into mammalian cells is facilitated by a family of glucose transport proteins known as GLUTs. Treatment of 3T3-L1 adipocytes with the Cdk5 inhibitor roscovitine strongly inhibits insulin-stimulated/GLUT4-mediated glucose transport. Inhibition of glucose uptake occurs within 2-6 min of the addition of roscovitine and is slowly reversed. The roscovitine treatment interferes with neither the translocation nor the insertion of GLUT4 into the plasma membrane. These studies support recent evidence showing that insulin-stimulated Cdk5 is implicated in the regulation of GLUT4-mediated glucose uptake in 3T3-L1 adipocytes.
