PGE(2), Ca(2+), and cAMP mediate ATP activation of Cl(-) channels in pigmented ciliary epithelial cells |
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Authors: | Fleischhauer J C Mitchell C H Peterson-Yantorno K Coca-Prados M Civan M M |
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Institution: | Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. |
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Abstract: | Purines regulate intraocular pressure. Adenosine activatesCl channels of nonpigmented ciliary epithelial cellsfacing the aqueous humor, enhancing secretion. Tamoxifen and ATPsynergistically activate Cl channels of pigmented ciliaryepithelial (PE) cells facing the stroma, potentially reducing netsecretion. The actions of nucleotides alone on Cl channelactivity of bovine PE cells were studied by electronic cell sorting,patch clamping, and luciferin/luciferase ATP assay. Clchannels were activated by ATP > UTP, ADP, and UDP, but not by 2-methylthio-ATP, all at 100 µM. UTP triggered ATP release. The second messengers Ca2+, prostaglandin (PG)E2,and cAMP activated Cl channels without enhancing effectsof 100 µM ATP. Buffering intracellular Ca2+activity with1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acidor blocking PGE2 formation with indomethacininhibited ATP-triggered channel activation. The Rp stereoisomerof 8-bromoadenosine 3',5'-cyclic monophosphothioate inhibited proteinkinase A activity but mimicked 8-bromoadenosine 3',5'-cyclicmonophosphate. We conclude that nucleotides can act at >1 P2Yreceptor to trigger a sequential cascade involving Ca2+,PGE2, and cAMP. cAMP acts directly on Clchannels of PE cells, increasing stromal release and potentially reducing net aqueous humor formation and intraocular pressure. |
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