[The molecular mechanism of vasospasm and the attenuation by fasudil].
Increase in cytosolic Ca2+ concentration and phosphorylation of myosin light chain (MLC) are key steps of normal and abnormal contractility in smooth muscle. In pathological condition like vasospasm, artery exhibits a hyperreactive contraction associated with an enhanced and sustained MLC phosphorylation, particularly diphosphorylation (Thr18/Ser19). Phosphorylation levelis regulated by a balance between phosphorylation and dephosphorylation. Recent studies propose that myosin phosphatase activity is regulated through the phosphorylation of 130K-myosin binding subunit (MBS130K) of the myosin phosphatase in smooth muscle. It is known that in normar artery, receptor agonists like PGF2 alpha induce certain contraction of smooth muscle associated with MLC diphosphorylation. We recently confirm that this PGF2 alpha stimulation also evokes the phosphorylation of MBS130K and fasudil, Rho-kinase inhibitor, inhibits this phosphorylation in parallel with MLC phosphorylation. Furthermore, we reveal that in vasospastic artery, Rho-kinase activity is augmented to induce high level phosphorylation of MBS130K. In this study, we also confirm that phosphorylation of MBS130K is Rho-kinase-dependent and its site is Thr654 residue. Now we speculate that fasudil may shift the phosphorylation-dephosphorylation cycle to dephosphorylation side through the inhibition of Thr654phosphorylation in MBS130K. These results also suggest that augmented activation of Rho-kinase may be involved in the pathophysiology of vasospasm associated with MLC diphosphorylation.
Seto
M
M
Institute for Life Science Research, Asahi Chemical Industry Co., Ltd., Fuji, Japan.
Takuwa
Y
Y
Sasaki
Y
Y
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020301:Vasospasm, Intracranial / Q000188:drug therapy
D018994:Myosin Light Chains; D014665:Vasodilator Agents; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049347:fasudil