ML-7 and W-7 facilitate thromboxane A2-mediated Ca2+ mobilization in rabbit platelets.
The effects of 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine (ML-7), a myosin light chain kinase inhibitor, and (N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a calmodulin antagonist, on thromboxane A2 receptor-mediated signal transduction were examined in rabbit washed platelets. ML-7 and W-7 at 10-30 microM slightly potentiated the aggregation induced by a thromboxane A2 receptor agonist, 9,11-dideoxy-9 alpha,11 alpha- epoxymethanoprostaglandin F2 alpha (U46619), in spite of their known inhibitory actions. ML-7 and W-7 concentration-dependently enhanced U46619-induced phosphoinositide hydrolysis and the increase in internal free Ca2+ concentration in the presence or absence of external Ca2+. While ML-7 and W-7 inhibited basal GTPase activity, they augmented U46619-induced activation of GTPase in a concentration-dependent manner. The present results suggest that ML-7 and W-7 enhance thromboxane A2 receptor-mediated signal transduction at the receptor/G protein coupling, leading to the enhancement of phosphoinositide hydrolysis and Ca2+ mobilization, independently of the inhibition of myosin light chain kinase or calmodulin.
Ohkubo
S
S
Department of Pharmaceutical Molecular Biology, Tohoku University, Aoba, Sendai, Japan.
Nakahata
N
N
Ohizumi
Y
Y
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000494:pharmacology*
D001381:Azepines; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D013449:Sulfonamides; C070571:ML 7; D004533:Egtazic Acid; D013928:Thromboxane A2; C017967:W 7; D002118:Calcium