TY - JOUR
T1 - Molecular mechanisms of Ca(2+) signaling in neurons induced by the S100A4 protein
AU - Kiryushko, Darya
AU - Novitskaya, Vera
AU - Soroka, Vladislav
AU - Klingelhofer, Jorg
AU - Lukanidin, Eugene
AU - Berezin, Vladimir
AU - Bock, Elisabeth
N1 - Keywords: Animals; Calcium; Calcium Channel Blockers; Calcium Channels; Calcium Signaling; Cell Membrane; Cells, Cultured; Dimerization; GAP-43 Protein; Heparan Sulfate Proteoglycans; Humans; Mice; Neurites; Neurons; Phosphatidylinositol Diacylglycerol-Lyase; Phosphorylation; Rats; Receptors, G-Protein-Coupled; S100 Proteins; Signal Transduction
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
U2 - 10.1128/MCB.26.9.3625-3638.2006
DO - 10.1128/MCB.26.9.3625-3638.2006
M3 - Journal article
C2 - 16612001
SN - 0270-7306
VL - 26
SP - 3625
EP - 3638
JO - Molecular and Cellular Biology
JF - Molecular and Cellular Biology
IS - 9
ER -