kn-93 and tautomycin

Axon pathfinding depends on attractive and repulsive turning of growth cones to extracellular cues. Localized cytosolic Ca2+ signals are known to mediate the bidirectional responses, but downstream mechanisms remain elusive. Here, we report that calcium-calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) phosphatase provide a switch-like mechanism to control the direction of Ca(2+)-dependent growth cone turning. A relatively large local Ca2+ elevation preferentially activates CaMKII to induce attraction, while a modest local Ca2+ signal predominantly acts through CaN and phosphatase-1 (PP1) to produce repulsion. The resting level of intracellular Ca2+ concentrations also affects CaMKII/CaN operation: a normal baseline allows distinct turning responses to different local Ca2+ signals, while a low baseline favors CaN-PP1 activation for repulsion. Moreover, the cAMP pathway negatively regulates CaN-PP1 signaling to inhibit repulsion. Finally, CaMKII/CaN-PP1 also mediates netrin-1 guidance. Together, these findings establish a complex Ca2+ mechanism that targets the balance of CaMKII/CaN-PP1 activation to control distinct growth cone responses.

Topics: Animals; Benzylamines; Calcineurin; Calcium; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Chlorocebus aethiops; COS Cells; Cyclic AMP; Cyclic GMP; Cyclosporine; Dose-Response Relationship, Drug; Drug Interactions; Egtazic Acid; Embryo, Mammalian; Embryo, Nonmammalian; Enzyme Inhibitors; Growth Cones; Humans; Models, Neurological; Nerve Growth Factors; Netrin-1; Neurons; Nitriles; Okadaic Acid; Phosphoprotein Phosphatases; Photolysis; Protein Phosphatase 1; Pyrans; Pyrethrins; Semaphorin-3A; Spinal Cord; Spiro Compounds; Sulfonamides; Time Factors; Tumor Suppressor Proteins; Xenopus