11 research outputs found
The multidrug resistance inhibitor 8-(4-chlorophenyl)-5-methyl-1 8-[(2Z)-pent-2-en-1-2 yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one diltiazem-like compound inhibits the ABCC6 transporter.
Extracellular ATP Regulates CD73 and ABCC6 Expression in HepG2 Cells
The ATP-binding cassette sub-family C member 6 transporter (ABCC6) is an ATP
dependent transporter mainly found in the basolateral plasma membrane of hepatic
and kidney cells. Mutations in ABCC6 gene were associated to the Pseudoxanthoma
elasticum (PXE), an autosomal recessive disease characterized by a progressive ectopic
calcification of elastic fibers in dermal, ocular, and vascular tissues. It is reported that
the over-expression of ABCC6 in HEK293 cells results in the cellular efflux of ATP and
other nucleoside triphosphates, which in turn are rapidly converted into nucleoside
monophosphates and pyrophosphate (PPi). Since PPi is an inhibitor of mineralization,
it was proposed that the absence of circulating PPi in PXE patients results in the ectopic
mineralization, a typical feature of PXE. In the extracellular environment, ATP is converted,
not only into pyrophosphate, but also into AMP by an ectonucleosidase, which in turn
is transformed into adenosine and phosphate. ABCC6 protein is thus involved in the
production of extracellular adenosine and therefore it could have a role in the activation
of the purinergic system. In the liver, purinergic signaling has been shown to regulate
key basic cellular functions. Our previous studies showed that in ABCC6 knockdown
HepG2 cells the expression of some genes, related with the calcification processes,
is dysregulated. In this study, experiments have been carried out in order to verify if
ABCC6, besides supplying the pyrophosphate required to prevent the mineralization of
soft tissues, also plays a role in the activation of the purinergic system. For this purpose,
the transport activity of ABCC6 was blocked with Probenecid and the expression of
ABCC6 and NT5E was analyzed with real time PCR and western blotting. The results of
this study showed that both proteins are downregulated in the presence of Probenecid
and upregulated in the presence of adenosine or ATP