Ca2+-Dependent Regulation of Rho GTPases Triggers Turning of Nerve Growth Cones

• Published in: The Journal of neuroscience 2005-03, Vol.25 (9), p.2338-2347
• Main Authors: Jin, Ming, Guan, Chen-bing, Jiang, Yun-ai, Chen, Gang, Zhao, Chun-tao, Cui, Kai, Song, Yuan-quan, Wu, Chien-ping, Poo, Mu-ming, Yuan, Xiao-bing
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Proteins - pharmacology; Bacterial Toxins - pharmacology; Blotting, Western - methods; Brain-Derived Neurotrophic Factor - pharmacology; Calcium - metabolism; cdc42 GTP-Binding Protein - pharmacology; Cell Line; Chelating Agents - pharmacology; Development/Plasticity/Repair; Diagnostic Imaging - methods; Dose-Response Relationship, Drug; Drug Interactions; Egtazic Acid - analogs & derivatives; Egtazic Acid - pharmacology; Embryo, Nonmammalian; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Green Fluorescent Proteins - pharmacology; Growth Cones - drug effects; Growth Cones - physiology; Humans; Nerve Growth Factors - pharmacology; Netrin-1; Neurons - cytology; Neurons - physiology; rho GTP-Binding Proteins - metabolism; Ryanodine - pharmacology; Spinal Cord - cytology; Thapsigargin - pharmacology; Time Factors; Transfection - methods; Tumor Suppressor Proteins - pharmacology; Xenopus
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4889-04.2005

Cytoplasmic Ca2+ elevation and changes in Rho GTPase activity are both known to mediate axon guidance by extracellular factors, but the causal relationship between these two events has been unclear. Here we show that direct elevation of cytoplasmic Ca2+ by extracellular application of a low concentration of ryanodine, which activated Ca2+ release from intracellular stores, upregulated Cdc42/Rac, but downregulated RhoA, in cultured cerebellar granule cells and human embryonic kidney 293T cells. Chemoattractive turning of the growth cone triggered by a gradient of ryanodine was blocked by overexpression of mutant forms of Cdc42 but not of RhoA in Xenopus spinal cord neurons. Furthermore, Ca2+-induced GTPase activity correlated with activation of protein kinase C and required a basal activity of Ca2+/calmodulin-dependent protein kinase II. Thus, Rho GTPases may mediate axon guidance by linking upstream Ca2+ signals triggered by guidance factors to downstream cytoskeletal rearrangements.