Transient receptor potential canonical 5 channels activate Ca 2+/calmodulin kinase Iγ to promote axon formation in hippocampal neurons

Monika A. Davare, Dale A. Fortin, Takeo Saneyoshi, Sean Nygaard, Stefanie Kaech, Gary Banker, Thomas R. Soderling, Gary A. Wayman

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70 Scopus citations


Functionality of neurons is dependent on their compartmentalized polarization of dendrites and an axon. The rapid and selective outgrowth of one neurite, relative to the others, to form the axon is critical in initiating neuronal polarity. Axonogenesis is regulated in part by an optimal intracellular calcium concentration. Our investigation of Ca2+-signaling pathways involved in axon formation using cultured hippocampal neurons demonstrates a role for Ca2+/calmodulin kinase kinase (CaMKK) and its downstream target Ca2+/calmodulin kinase I (CaMKI). Expression of constitutively active CaMKI induced formation of multiple axons, whereas blocking CaMKK or CaMKI activity with pharmacological, dominant-negative, or short hairpin RNA (shRNA) methods significantly inhibited axon formation. CaMKK signals via the γ-isoform of CaMKI as shRNA to CaMKIγ, but not the other CaMKI isoforms, inhibited axon formation. Furthermore, overexpression of wild-type CaMKIγ, but not a mutant incapable of membrane association, accelerated the rate of axon formation. Pharmacological or small interfering RNA inhibition of transient receptor potential canonical 5 (TRPC5) channels, which are present in developing axonal growth cones, suppressed CaMKK-mediated activation of CaMKIγ as well as axon formation. We demonstrate using biochemical fractionation and immunocytochemistry that CaMKIγ and TRPC5 colocalize to lipid rafts. These results are consistent with a model in which highly localized calcium influx through the TRPC5 channels activates CaMKK and CaMKIγ, which subsequently promote axon formation.

Original languageEnglish (US)
Pages (from-to)9794-9808
Number of pages15
JournalJournal of Neuroscience
Issue number31
StatePublished - Aug 5 2009

ASJC Scopus subject areas

  • Neuroscience(all)


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