Polysialic acid limits choline acetyltransferase activity induced by brain-derived neurotrophic factor.
Choline acetyltransferase (ChAT), the enzyme synthesizing acetylcholine, is known to be activated by brain derived neurotrophic factor (BDNF). We found that the specific removal of the carbohydrate polysialic acid (PSA) significantly increased BDNF-induced ChAT-activity in embryonic septal neurons. Using a p75 neurotrophin receptor (p75(NTR)) function-blocking antibody and K252a, a-pan tropomyosin related kinase (Trk) inhibitor, we demonstrate that BDNF-induced ChAT activity requires the stimulation of p75(NTR) and TrkB. PSA removal drastically increased radioactive iodinated ([(125)I])BDNF's maximal binding capacity (Bmax), derived from concentrations of [(125)I]BDNF ranging from 1 pM to 3.2 nM. In the presence of unlabeled nerve growth factor to prevent the binding of [(125)I]BDNF to p75(NTR) sites, the impact of PSA removal on the binding capacity of [(125)I]BDNF was greatly reduced. In conclusion, PSA limits BDNF-induced ChAT activity and BDNF-receptor interactions. BDNF-induced ChAT activity is TrkB and p75(NTR) dependent, and upon PSA removal the additional binding of BDNF to its receptors, especially p75(NTR), likely contributes to the maximal ChAT activity observed. In vivo, the ontogenetic loss of PSA in the postnatal period may allow more interactions between BDNF and its receptors to increase ChAT activity and assure the proper development of the cholinergic septal neurons.
Burgess
Alison
A
Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Aubert
Isabelle
I
D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006026:Glycoside Hydrolases / Q000378:metabolism; D007150:Immunohistochemistry; D007457:Iodine Radioisotopes; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D012794:Sialic Acids / Q000494:pharmacology*
D019208:Brain-Derived Neurotrophic Factor; D007457:Iodine Radioisotopes; D020800:Receptor, Nerve Growth Factor; D012794:Sialic Acids; C021319:polysialic acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D002795:Choline O-Acetyltransferase; D020813:Receptor, trkB; D006026:Glycoside Hydrolases; C090534:endo-alpha-sialidase