Extracellular adenosine triphosphate affects neural cell adhesion molecule(NCAM)-mediated cell adhesion and neurite outgrowth

The neural cell adhesion molecule (NCAM) plays an important role in synapti c plasticity in embryonic and adult brain. Recently, it has been demonstrat ed that NCAM is capable of binding and hydrolyzing extracellular ATP, The p urpose of the present study was to evaluate the role of extracellular ATP i n NCAM-mediated cellular adhesion and neurite outgrowth. We here show that extracellularly added adenosine triphosphate (ATP) and its structural analo gues, adenosine-5'-O-(3-thiothiophosphate), beta,gamma-methylenadenosine-5' -triphosphate, beta,gamma-imidoadenosine-5-triphosphate, and UTP, in varyin g degrees inhibited aggregation of hippocampal neurons. Rat glial BT4Cn cel ls are unable to aggregate when grown on agar but acquire this capacity whe n transfected with NCAM. However, addition of extracellular ATP to NCAM-tra nsfected BT4Cn cells inhibited aggregation. Furthermore, neurite outgrowth from hippocampal neurons in cultures allowing NCAM-homophilic interactions was inhibited by addition of extracellular nucleotides, These findings indi cate that NCAM-mediated adhesion may be modulated by extracellular ATP, Mor eover, extracellularly added ATP stimulated neurite outgrowth from hippocam pal neurons under conditions non-permissive for NCAM-homophilic interaction s, and neurite outgrowth stimulated by extracellular ATP could be inhibited by a synthetic peptide corresponding to the so-called cell adhesion molecu le homology domain (CHD) of the fibroblast growth factor receptor (FGFR) an d by FGFR antibodies binding to this domain. Antibodies against the fibrone ctin type-III homology modules of NCAM, in which a putative site for ATP bi nding and hydrolysis is located, also abolished the neurite outgrowth-promo ting effect of ATP, The non-hydrolyzable analogues of ATP all strongly inhi bited neurite outgrowth. Our results indicate that extracellular ATP may be involved in synaptic plasticity through a modulation of NCAM-mediated adhe sion and neurite outgrowth. J, Neurosci, Res. 57:207-218, 1999, (C) 1999 Wi ley-Liss, Inc.