Signal transduction of ET-1 in contraction of cerebral arteries.
The signaling pathways of endothelin-1-induced contraction, including the role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC) and RhoA/Rho-kinase were studied using rabbit basilar arteries by isometric tension and Western blot. The following results were observed: (1) endothelin-1 produced phosphorylation of MAPK and RhoA and contraction by activation of endothelin-A but not endothelin-B receptors; (2) MAPK inhibitors, PD 98059 and U0126, PTK inhibitor, genistein, Src kinase inhibitor, damnacanthal, and Janus tyrosine kinase (JAK2) inhibitor, AG-490, abolished endothelin-1-induced contraction and MAPK immunoreactivity; (3) PTK inhibitor, staurosporine, and phosphatidylinositol 3-kinase (PI- 3K) inhibitor wortmannin abolished endothelin-1 induced contraction but not MAPK immunoreactivity; (4) Rho-kinase inhibitor, Y-27632, reduced endothelin-1-induced contraction; (5) PI-3K inhibitor, wortmannin, but not PKC and PTK inhibitors, reduced endothelin-1-induced RhoA activation; (6) endothelin-1 increased the level of myosin light chain (MLC) phosphorylation, and Rho-kinase inhibitor, Y-27632, reduced the effect of endothelin- 1 on MLC phosphorylation. This study demonstrated that three signaling pathways Src-JAK2-PTK-MAPK, PI-3K-RhoA-Rhokinase- MLC and PKC all contribute to endothelin-1-induced contraction in the rabbit basilar artery. MAPK is downstream of PTK, Src and JAK pathways. PI-3 kinase and MLC might be the upstream and downstream factors of RhoA activation.
Zubkov
Alexander
A
Department of Neurosurgery, University of Mississippi Medical Center, Jackson, USA.
Miao
Liyan
L
Zhang
John
J
D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015153:Blotting, Western; D019332:Endothelin-1 / Q000378:metabolism*; D066298:In Vitro Techniques; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009213:Myography; D018994:Myosin Light Chains / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D019332:Endothelin-1; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D019869:Phosphatidylinositol 3-Kinases; D053614:Janus Kinase 2; D019061:src-Family Kinases; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein