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The Journal of Neuroscience, August 5, 2009, 29(31):9794-9808; doi:10.1523/JNEUROSCI.1544-09.2009

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Development/Plasticity/Repair
Transient Receptor Potential Canonical 5 Channels Activate Ca2+/Calmodulin Kinase I{gamma} to Promote Axon Formation in Hippocampal Neurons

Monika A. Davare,1 Dale A. Fortin,1 Takeo Saneyoshi,3 Sean Nygaard,1 Stefanie Kaech,2 Gary Banker,2 Thomas R. Soderling,1 and Gary A. Wayman4

1Vollum Institute and 2Jungers Center, Oregon Health & Science University, Portland, Oregon 97223, 3National Institute of Advanced Industrial Science and Technology, Biological Information Research Center, Aomi, Tokyo 135-0064, Japan, and 4Department of Veterinary Comparative Anatomy, Physiology and Pharmacology, Washington State University, Pullman, Washington 99163

Correspondence should be addressed to Thomas R. Soderling, Vollum Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: soderlit{at}ohsu.edu

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 {gamma}-isoform of CaMKI as shRNA to CaMKI{gamma}, but not the other CaMKI isoforms, inhibited axon formation. Furthermore, overexpression of wild-type CaMKI{gamma}, 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 CaMKI{gamma} as well as axon formation. We demonstrate using biochemical fractionation and immunocytochemistry that CaMKI{gamma} 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 CaMKI{gamma}, which subsequently promote axon formation.

Received March 31, 2009; revised May 20, 2009; accepted June 20, 2009.

Correspondence should be addressed to Thomas R. Soderling, Vollum Institute, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: soderlit{at}ohsu.edu






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