Is the light chain subcellular localization an important factor in botulinum toxin duration of action?
Botulinum neurotoxins (BoNT) are therapeutic proteins that are specific, potent, and effective. They are highly specific in binding to motor neurons but do not bind to other non-neuronal cells. These proteins are zinc-dependent endopeptidases that inhibit exocytosis by specific cleavage of the SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein-receptor) proteins involved in vesicle docking and fusion. The therapeutic effect of BoNT/A in humans lasts from 3 to 12 months, depending upon the condition treated. Data from animal and cell culture models suggests that the long-lasting duration of inhibition of neurotransmitter release induced by BoNT/A maybe due to the persistence of the endopeptidase activity of the light chain (LC/A) in cells, interactions of the cleaved substrates, and/or the response of the nerve to the temporary disruption of communication with its target tissue. We have analyzed the subcellular localization of the light chains from serotypes A, B, and E and have demonstrated that each light chain displays a distinct distribution within cells. LC/A localizes at the plasma membrane, LC/B is dispersed throughout the cell including the nucleus, and LC/E is mainly cytosolic. Localization is similar in non-neuronal cell lines, suggesting that the signals involved in proper subcellular localization are within the LC sequences and the moiety the light chain interacts with is present in both neuronal and non-neuronal cells.
Fernández-Salas
Ester
E
Neurotoxin Research Program, Department of Biological Sciences, Allergan Inc, Irvine, California 92612, USA.
Ho
Helen
H
Garay
Patton
P
Steward
Lance E
LE
Aoki
K Roger
KR
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001905:Botulinum Toxins / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D003001:Cloning, Molecular / Q000379:methods; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005089:Exocytosis / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D006801:Humans; D007668:Kidney; D008164:Luminescent Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009498:Neurotoxins / Q000145:classification / Q000378:metabolism / Q000494:pharmacology*; D011233:Precipitin Tests / Q000379:methods; D051381:Rats; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25; D013997:Time Factors; D014162:Transfection / Q000379:methods
D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; C494208:SNAP25 protein, human; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D049452:Green Fluorescent Proteins; D001905:Botulinum Toxins; D005947:Glucose