A CaMKII/calcineurin Switch Controls the Direction of Ca(2+)-dependent Growth Cone Guidance

Neuron. 2004 Sep 16;43(6):835-46. doi: 10.1016/j.neuron.2004.08.037.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

  • Benzylamines
  • Enzyme Inhibitors
  • KN 92
  • NTN1 protein, human
  • Nerve Growth Factors
  • Nitriles
  • Pyrans
  • Pyrethrins
  • Semaphorin-3A
  • Spiro Compounds
  • Sulfonamides
  • Tumor Suppressor Proteins
  • tautomycin
  • KN 93
  • Netrin-1
  • Okadaic Acid
  • 2-nitrophenyl-EGTA
  • decamethrin
  • Egtazic Acid
  • Cyclosporine
  • Cyclic AMP
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 1
  • Cyclic GMP
  • Calcium