A CaMKII/calcineurin switch controls the direction of Ca 2+-dependent growth cone guidance

Zhexing Wen, Carmine Guirland, Guo Li Ming, James Q. Zheng

Research output: Contribution to journalArticlepeer-review

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 Ca2+-dependent growth cone turning. A relatively large local Ca2+ elevation preferentially activates CaMKII to induce attraction, while a modest local Ca2+ signal predominately 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.

Original languageEnglish (US)
Pages (from-to)835-846
Number of pages12
JournalNeuron
Volume43
Issue number6
DOIs
StatePublished - Sep 16 2004

ASJC Scopus subject areas

  • Neuroscience(all)

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