Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 277, Issue 35, Pages 31390-31400Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110714200
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Rat brain capillary endothelial (B10) cells express an unidentified nucleotide receptor linked to adenylyl cyclase inhibition. We show that this receptor in B10 cells is identical in sequence to the P2Y(12) ADP receptor (P2Y(T)) of platelets. When expressed heterologously, 2-methylthio-ADP (2-MeSADP; EC50, 2 nm), ADP, and adenosine 5'-O-(2-thio)diphosphate were agonists of cAMP decrease, and 2-propylthio-D-beta,gamma-difluoromethylene-ATP was a competitive antagonist (K,, 28 nm), as in platelets. However, 2-methylthio-ATP (2-MeSATP) (EC50, 0.4 nm), ATP (1.9 mum), and 2-chloro-ATP (190 nm), antagonists in the platelet, were also agonists. 2-Me- SADP activated (EC50, 0.1 nm) GIRK1/GIRK2 inward rectifier K+ channels when co-expressed with P2Y(12) receptors in sympathetic neurons. Surprisingly, P2Y(1) receptors expressed likewise gave that response; however, a full inactivation followed, absent with P2Y(12) receptors. A new P2Y(12)-mediated transduction was found, the closing of native N-type Ca2+ channels; again both 2-MeSATP and 2-MeSADP are agonists (EC50, 0.04 and 0.1 nm, respectively). That action, like their cAMP response, was pertussis toxin-sensitive. The Ca2+ channel inhibition and K+ channel activation are mediated by betay subunit release from a heterotrimeric G-protein. Galpha subunit types in B10 cells were also identified. The presence in the brain capillary endothelial cell of the P2Y(12) receptor is a significant extension of its functional range.
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