Okadaic acid inhibits angiotensin II stimulation of Ins(1,4,5)P3 and calcium signalling in rat hepatocytes.
OKA2 and CL-A significantly inhibit the ability of angiotensin II, ATP and vasopressin to raise [Ca2+]i in rat hepatocytes, with a partial inhibition of the initial spike, and a complete inhibition of the following plateau. In contrast, the [Ca2+]i response to thapsigargin, which releases intracellular calcium stores through a mechanism independent of inositol phosphates, is much less affected. The ability of angiotensin II to stimulate Ins(1,4,5)P3 production is also reduced by OKA, with kinetics consistent with the inhibited [Ca2+]i response. Since OKA and CL-A are potent and selective inhibitors of phosphoprotein phosphatases, these results provide further evidence that agonist-stimulated Ins(1,4,5)P3 signalling can be inhibited by protein phosphorylation.
Mattingly
R R
RR
Department of Pharmacology, University of Virginia School of Medicine, Charlottesville 22908.
Garrison
J C
JC
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008387:Marine Toxins; D019319:Okadaic Acid; D010080:Oxazoles / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*
D004988:Ethers, Cyclic; D007476:Ionophores; D008387:Marine Toxins; D010080:Oxazoles; D000804:Angiotensin II; D019319:Okadaic Acid; C059041:calyculin A; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium