A CaMKII/calcineurin switch controls the direction of Ca(2+)-dependent growth cone guidance.
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.
Wen
Zhexing
Z
Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Guirland
Carmine
C
Ming
Guo-Li
GL
Zheng
James Q
JQ
D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D019556:COS Cells; D019703:Calcineurin / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000494:pharmacology; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009570:Nitriles; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010782:Photolysis; D054645:Protein Phosphatase 1; D011714:Pyrans / Q000494:pharmacology; D011722:Pyrethrins / Q000494:pharmacology; D040121:Semaphorin-3A / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology* / Q000196:embryology; D013141:Spiro Compounds / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D025521:Tumor Suppressor Proteins; D014981:Xenopus; D000096926:Benzenesulfonamides
D001596:Benzylamines; D019703:Calcineurin; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000242:Cyclic AMP; D006152:Cyclic GMP; D016572:Cyclosporine; D004533:Egtazic Acid; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D000075388:Netrin-1; D009570:Nitriles; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D011714:Pyrans; D011722:Pyrethrins; D040121:Semaphorin-3A; D013141:Spiro Compounds; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; C425780:KN 92; C000617351:NTN1 protein, human; C053079:tautomycin; C072105:KN 93; D000096926:Benzenesulfonamides; C085112:2-nitrophenyl-EGTA; C017180:decamethrin