title: Involvement of extracellular Ca2+ influx and epidermal growth factor receptor tyrosine kinase transactivation in endothelin-1-induced arachidonic acid release.
abstract: 1. Endothelin-1 (ET-1) activates two types of Ca(2+)-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca(2+) channel (SOCC) in vascular smooth muscle cells (VSMCs). These channels can be distinguished by their sensitivity to Ca(2+)-channel blockers, SK&F 96365 and LOE 908. LOE 908 is sensitive to NSCC-1 and NSCC-2, and SK&F 96365 is sensitive to NSCC-2 and SOCC. Moreover, these channels play essential roles in ET-1-induced epidermal growth factor receptor protein tyrosine kinase (EGFR PTK) transactivation. The main purpose of the present study was to demonstrate the involvement of EGFR PTK transactivation in ET-1-induced arachidonic acid release in VSMCs. 2. Both SK&F 96365 and LOE 908 inhibited ET-1-induced arachidonic acid release with the IC(50) values correlated to those of ET-1-induced Ca(2+) influx. Moreover, combined treatment with these blockers abolished ET-1-induced arachidonic acid release. 3. AG1478, a specific inhibitor of EGFR PTK, inhibited ET-1-induced arachidonic acid release and extracellular signal-regulated kinase 1 and 2 (ERK1/2). The IC(50) values of AG1478 for ET-1-induced arachidonic acid release and ERK1/2 correlated well with those for ET-1-induced EGFR PTK transactivation. 4. Mitogen-activated protein kinase kinase inhibitor, PD 98059, inhibited ET-1-induced arachidonic acid release. The IC(50) values of PD 98059 for ET-1-induced arachidonic acid release were similar to those for ET-1-induced ERK1/2 activity. In contrast, PD 98059 failed to inhibit ET-1-induced EGFR PTK transactivation. 5. These results indicate that (1) extracellular Ca(2+) influx through NSCCs and SOCC plays important roles for ET-1-induced arachidonic acid release, (2) EGFR PTK transactivation/ERK1/2 pathways are involved in ET-1-induced arachidonic acid release.
authors.affiliation: Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. ykawanabe@rics.bwh.harvard.edu
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kawanabe
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nozaki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Tomoh
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D015533:Transcriptional Activation
chemical_list: D015220:Calcium Channels; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016718:Arachidonic Acid; D066246:ErbB Receptors