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Vol. 17, Issue 5, 2278-2286, May 2006

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Neural Cell Adhesion Molecule Induces Intracellular Signaling via Multiple Mechanisms of Ca²⁺ Homeostasis

Protein Laboratory, Institute of Molecular Pathology, Panum Institute, DK-2200 Copenhagen N, Denmark

Submitted October 27, 2005; Revised January 17, 2006; Accepted February 16, 2006
Monitoring Editor: Marianne Bronner-Fraser

The neural cell adhesion molecule (NCAM) plays a pivotal role in the development of the nervous system, promoting neuronal differentiation via homophilic (NCAM–NCAM) as well as heterophilic (NCAM-fibroblast growth factor receptor [FGFR]) interactions. NCAM-induced intracellular signaling has been shown to affect and be dependent on the cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i). However, the molecular basis of this remains unclear. In this study, we determined [Ca²⁺]_i regulating mechanisms involved in intracellular signaling induced by NCAM. To mimic the effect of homophilic NCAM interaction on [Ca²⁺]_i in vitro, we used a peptide derived from a homophilic binding site of NCAM, termed P2, which triggers signaling cascades similar to those activated by NCAM–NCAM interaction. We found that P2 increased [Ca²⁺]_i in primary hippocampal neurons. This effect depended on two signaling pathways. The first pathway was associated with activation of FGFR, phospholipase C, and production of diacylglycerol, and the second pathway involved Src-family kinases. Moreover, NCAM-mediated Ca²⁺ entry required activation of nonselective cation and T-type voltage-gated Ca²⁺ channels. These channels, together with the Src-family kinases, were also involved in neuritogenesis induced by physiological, homophilic NCAM interactions. Thus, unanticipated mechanisms of Ca²⁺ homeostasis are shown to be activated by NCAM and to contribute to neuronal differentiation.

Abbreviations used: 2-AG, 2-arachidonoyl glycerol; AA, arachidonic acid; DAG, diacylglycerol; GAP, growth-associated protein; NSCC, nonselective cation channel; PLC, phospholipase C; RTK, receptor tyrosine kinase; TRP, transient receptor potential; VDCC, voltage-dependent Ca²⁺ channel.

Address correspondence to: Darya Kiryushko (darya{at}plab.ku.dk).

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