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Molecular and Cellular Biology, May 2006, p. 3625-3638, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3625-3638.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Molecular Mechanisms of Ca2+ Signaling in Neurons Induced by the S100A4 Protein

Darya Kiryushko,1,{dagger}* Vera Novitskaya,1,{dagger} Vladislav Soroka,1 Jorg Klingelhofer,2 Eugene Lukanidin,2 Vladimir Berezin,1 and Elisabeth Bock1

Protein Laboratory, Institute of Molecular Pathology, Panum Institute Bld. 6.2, Blegdamsvej 3C, DK-2200 Copenhagen N, Denmark,1 Department of Molecular Cancer Biology, Institute of Molecular Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen Ø, Denmark2

Received 17 August 2005/ Returned for modification 13 October 2005/ Accepted 8 February 2006

The S100A4 protein belongs to the S100 family of vertebrate-specific proteins possessing both intra- and extracellular functions. In the nervous system, high levels of S100A4 expression are observed at sites of neurogenesis and lesions, suggesting a role of the protein in neuronal plasticity. Extracellular oligomeric S100A4 is a potent promoter of neurite outgrowth and survival from cultured primary neurons; however, the molecular mechanism of this effect has not been established. Here we demonstrate that oligomeric S100A4 increases the intracellular calcium concentration in primary neurons. We present evidence that both S100A4-induced Ca2+ signaling and neurite extension require activation of a cascade including a heterotrimeric G protein(s), phosphoinositide-specific phospholipase C, and diacylglycerol-lipase, resulting in Ca2+ entry via nonselective cation channels and via T- and L-type voltage-gated Ca2+ channels. We demonstrate that S100A4-induced neurite outgrowth is not mediated by the receptor for advanced glycation end products, a known target for other extracellular S100 proteins. However, S100A4-induced signaling depends on interactions with heparan sulfate proteoglycans at the cell surface. Thus, glycosaminoglycans may act as coreceptors of S100 proteins in neurons. This may provide a mechanism by which S100 proteins could locally regulate neuronal plasticity in connection with brain lesions and neurological disorders.

* Corresponding author. Mailing address: Protein Laboratory, Panum Institute, Blegdamsvej 3C, Bld. 6.2, Copenhagen 2200N, Denmark. Phone: (45) 35 32 73 30. Fax: (45) 35 36 01 16. E-mail: darya{at}plab.ku.dk.

{dagger} D. Kiryushko and V. Novitskaya contributed equally to this work.

Molecular and Cellular Biology, May 2006, p. 3625-3638, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3625-3638.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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