title: Molecular mechanisms of Ca(2+) signaling in neurons induced by the S100A4 protein.
abstract: 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 Ca(2+) signaling and neurite extension require activation of a cascade including a heterotrimeric G protein(s), phosphoinositide-specific phospholipase C, and diacylglycerol-lipase, resulting in Ca(2+) entry via nonselective cation channels and via T- and L-type voltage-gated Ca(2+) 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.
authors.affiliation: Protein Laboratory, Panum Institute, Blegdamsvej 3C, Bld. 6.2, Copenhagen 2200N, Denmark. darya@plab.ku.dk
authors.forename: Darya
authors.initials: D
authors.lastname: Kiryushko
authors.forename: Vera
authors.initials: V
authors.lastname: Novitskaya
authors.forename: Vladislav
authors.initials: V
authors.lastname: Soroka
authors.forename: Jorg
authors.initials: J
authors.lastname: Klingelhofer
authors.forename: Eugene
authors.initials: E
authors.lastname: Lukanidin
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bock
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling; D002462:Cell Membrane; D002478:Cells, Cultured; D019281:Dimerization; D019922:GAP-43 Protein / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D043265:Phosphatidylinositol Diacylglycerol-Lyase / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000737:chemistry / Q000494:pharmacology*; D000067616:S100A12 Protein; D015398:Signal Transduction
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019922:GAP-43 Protein; D019812:Heparan Sulfate Proteoglycans; D043562:Receptors, G-Protein-Coupled; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; C077591:S100A4 protein, human; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D002118:Calcium