Geldanamycin specifically modulates thrombin-mediated morphological changes in mouse neuroblasts.
Regulation of neuronal morphology and extension of cell processes are required for normal synaptic connections and signaling. Thrombin, a serine protease, regulates neuronal morphological changes by activating protease activated receptor-1 (PAR-1), a seven-transmembrane G protein-coupled receptor. Thrombin-mediated morphological changes precede its diverse action on neurons, and the drugs that regulate these morphological changes have important therapeutic implications. The present study was carried out to evaluate the role of geldanamycin, a specific inhibitor of Hsp90 on thrombin-induced regulation of neuronal morphology. Incubation of mouse neuroblasts (NB2a) with geldanamycin prevented thrombin-mediated neurite retraction in a dose-dependent manner. Geldanamycin also blocked thrombin-induced activation of RhoA, a small GTP binding protein involved in the cytoskeletal signaling. To determine the specificity of geldanamycin action, its effect on lysophosphatidic acid (LPA)-induced morphological changes was examined. Geldanamycin did not have any effect on LPA-induced neurite retraction and RhoA activation indicating a specific role for this drug in the regulation of thrombin-mediated morphological changes.
Pai
Karnire Sadashiva
KS
Department of Microbiology & Molecular Genetics, University of California, Irvine, California 92697-4025, USA.
Cunningham
Dennis D
DD
D000818:Animals; D016227:Benzoquinones; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D047029:Lactams, Macrocyclic; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D016501:Neurites / Q000187:drug effects; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology*; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008246:Lysophospholipids; D011809:Quinones; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D013917:Thrombin; D020742:rhoA GTP-Binding Protein; C001277:geldanamycin