Geldanamycin specifically modulates thrombin‐mediated morphological changes in mouse neuroblasts

• Published in: Journal of neurochemistry 2002-02, Vol.80 (4), p.715-718
• Main Authors: Pai, Karnire Sadashiva, Cunningham, Dennis D.
• Format: Article
• Language: English
• Subjects: Animals; Benzoquinones; Biological and medical sciences; Cell Line; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Isolated neuron and nerve. Neuroglia; Lactams, Macrocyclic; lysophosphatidic acid (LPA); Lysophospholipids - pharmacology; Mice; morphology; Neurites - drug effects; Neuroblastoma - metabolism; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; protease activated receptor‐1 (PAR‐1); Quinones - pharmacology; Receptor, PAR-1; Receptors, Thrombin - metabolism; RhoA; rhoA GTP-Binding Protein - metabolism; Signal Transduction - drug effects; thrombin; Thrombin - pharmacology; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.0022-3042.2001.00761.x

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.