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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1665-1672
Dichotomous Regulation of Myosin Phosphorylation and Shape Change
by Rho-Kinase and Calcium in Intact Human Platelets
Markus Bauer,
Michaela Retzer,
Jonathan I. Wilde,
Petra Maschberger,
Markus Essler,
Martin Aepfelbacher,
Steve P. Watson, and
Wolfgang Siess
Institut für Prophylaxe und Epidemiologie der
Kreislaufkrankheiten, Klinikum Innenstadt, Universität
München, München, Germany; the Department of Pharmacology,
Oxford University, Oxford, UK; and Max von Pettenkofer-Institut,
Universität München, München, Germany.
Both Rho-kinase and the Ca2+/calmodulin-dependent
myosin light chain (MLC) kinase increase the phosphorylation of MLC. We
show that upon thrombin receptor stimulation by low-dose thrombin or the peptide ligand YFLLRNP, or upon thromboxane receptor activation by
U46619, shape change and MLC phosphorylation in human platelets proceed
through a pathway that does not involve an increase in cytosolic
Ca2+. Under these conditions, Y-27632, a specific
Rho-kinase inhibitor, prevented shape change and reduced the
stimulation of MLC-phosphorylation. In contrast, Y-27632 barely
affected shape change and MLC-phosphorylation by adenosine diphosphate
(ADP), collagen-related peptide, and ionomycin that were associated
with an increase in cytosolic Ca2+ and inhibited by
BAPTA-AM/EGTA treatment. Furthermore, C3 exoenzyme, which inactivates
Rho, inhibited preferentially the shape change induced by YFLLRNP
compared with ADP and ionomycin. The results indicate that the
Rho/Rho-kinase pathway is pivotal in mediating the MLC phosphorylation
and platelet shape change by low concentrations of certain G
protein-coupled platelet receptors, independent of an increase in
cytosolic Ca2+. Our study defines 2 alternate pathways,
Rho/Rho-kinase and Ca2+/calmodulin-regulated MLC-kinase,
that lead independently of each other through stimulation of
MLC-phosphorylation to the same physiological response in human
platelets (ie, shape change).
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