Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Benzylamines / pharmacology
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COS Cells
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Calcineurin / physiology*
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Calcium / metabolism*
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Calcium Signaling
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Cells, Cultured
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Chlorocebus aethiops
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / pharmacology
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Cyclic GMP / analogs & derivatives
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Cyclic GMP / pharmacology
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Cyclosporine / pharmacology
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Dose-Response Relationship, Drug
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Drug Interactions
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Egtazic Acid / analogs & derivatives
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Egtazic Acid / pharmacology
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Embryo, Mammalian
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Embryo, Nonmammalian
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Enzyme Inhibitors / pharmacology
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Growth Cones / drug effects
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Growth Cones / physiology*
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Humans
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Models, Neurological
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Nerve Growth Factors / pharmacology
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Netrin-1
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Neurons / cytology*
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Neurons / drug effects
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Neurons / physiology
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Nitriles
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Okadaic Acid / pharmacology
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Phosphoprotein Phosphatases / physiology
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Photolysis
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Protein Phosphatase 1
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Pyrans / pharmacology
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Pyrethrins / pharmacology
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Semaphorin-3A / pharmacology
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Spinal Cord / cytology*
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Spinal Cord / embryology
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Spiro Compounds / pharmacology
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Sulfonamides / pharmacology
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Time Factors
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Tumor Suppressor Proteins
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Xenopus
Substances
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Benzylamines
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Enzyme Inhibitors
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KN 92
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NTN1 protein, human
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Nerve Growth Factors
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Nitriles
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Pyrans
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Pyrethrins
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Semaphorin-3A
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Spiro Compounds
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Sulfonamides
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Tumor Suppressor Proteins
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tautomycin
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KN 93
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Netrin-1
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Okadaic Acid
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2-nitrophenyl-EGTA
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decamethrin
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Egtazic Acid
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Cyclosporine
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Cyclic AMP
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Calcineurin
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Phosphoprotein Phosphatases
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Protein Phosphatase 1
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Cyclic GMP
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Calcium