The mode of rabbit platelet shape change and aggregation induced by theonezolide-A, a novel polyketide macrolide, isolated from the Okinawan marine sponge Theonella sp.
Theonezolide-A (TZ-A), a novel polyketide macrolide, isolated from the Okinawan marine sponge Theonella sp., caused a marked platelet shape change at low concentrations (0.2-0.6 microM). Increasing concentrations of TZ-A to 6 microM or more caused shape change followed by a small but sustained aggregation. In a Ca(2+)-free solution, TZ-A-induced aggregation was markedly inhibited, although the marked shape change was still observed. Aggregation stimulated by TZ-A increased in a linear fashion with increasing Ca2+ concentrations from 0.1 to 3.0 mM. Furthermore TZ-A markedly enhanced 45Ca2+ uptake into platelets. Aggregation induced by TZ-A was inhibited by Arg-Gly-Asp-Ser, an inhibitor of fibrinogen binding to glycoprotein IIb-IIIa, H-7 and staurosporine, protein kinase C inhibitors, or genistein and tyrphostin A23, protein tyrosine kinase inhibitors, whereas shape change was blocked by genistein and tyrphostin A23. H-7 or staurosporine did not affect the TZ-A-induced shape change. These results suggest that TZ-A-induced platelet shape change is not dependent on external Ca2+, whereas TZ-A-induced aggregation is caused by an increase in Ca2+ permeability of the plasma membrane. It is also suggested that both aggregation and shape change induced by TZ-A are associated with protein phosphorylation by protein kinase C and tyrosine kinase.
Rho
M C
MC
Department of Pharmaceutical Molecular Biology, Faculty of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Park
Y H
YH
Sasaki
S
S
Ishibashi
M
M
Kondo
K
K
Kobayashi
J
J
Ohizumi
Y
Y
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology; D008297:Male; D010080:Oxazoles / Q000302:isolation & purification / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011161:Porifera / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011817:Rabbits; D013844:Thiazoles / Q000302:isolation & purification / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007529:Isoflavones; D010080:Oxazoles; D013844:Thiazoles; C104930:theonezolide A; D000244:Adenosine Diphosphate; D014700:Verapamil; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D002118:Calcium