Identification of Fibroblast Growth Factor Receptor 3 (FGFR3) as a Protein Receptor for Botulinum Neurotoxin Serotype A (BoNT/A)

Botulinum neurotoxin serotype a (bont/a) causes transient muscle paralysis by entering motor nerve terminals (mnts) where it cleaves the snare protein synaptosomal-associated protein 25 (snap25206) to yield snap25197. cleavage of snap25 results in blockage of synaptic vesicle fusion and inhibition of the release of acetylcholine. the specific uptake of bont/a into pre-synaptic nerve terminals is a tightly controlled multistep process,involving a combination of high and low affinity receptors. interestingly,the c-terminal binding domain region of bont/a,hc/a,is homologous to fibroblast growth factors (fgfs),making it a possible ligand for fibroblast growth factor receptors (fgfrs). here we present data supporting the identification of fibroblast growth factor receptor 3 (fgfr3) as a high affinity receptor for bont/a in neuronal cells. hc/a binds with high affinity to the two extra-cellular loops of fgfr3 and acts similar to an agonist ligand for fgfr3,resulting in phosphorylation of the receptor. native ligands for fgfr3; fgf1,fgf2,and fgf9 compete for binding to fgfr3 and block bont/a cellular uptake. these findings show that fgfr3 plays a pivotal role in the specific uptake of bont/a across the cell membrane being part of a larger receptor complex involving ganglioside- and protein-protein interactions. © 2013 jacky et al.