Botulinum Toxin: Mechanism of Action

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  • Botulinum toxin (BTX) is isolated and purified from cultures of Clostridium botulinum . Clostridia produce seven serotypes of BTX, denoted A-G, as well as tetanus toxin. The seven seroptyes have similar molecular structures, but differ in their intracellular targets and clinical durations of action. The toxin molecule is composed of a light and heavy chain, linked by a disulfide bond. The structure of both types A (shown here) and B (next slide) includes three domains, corresponding to the three stages in the toxin’s action: binding and internalization, translocation, and proteolytic activity. The purified toxin is surrounded by five proteins (not shown) which are believed to stabilize it and facilitate its passage through the gastrointestinal tract. These proteins are shed before internalization at the neuromuscular junction. Slide courtesy of Dr. Ray Stevens, The Scripps Research Institute and Institute for Childhood and Neglected Diseases.
  • Botulinum toxin binds to specific acceptors on the neuronal membrane at the neuromuscular junction (1). Internalization is by endocytosis (2), which is followed by acidification of the endocytic vesicle (3). This pH change induces structural changes that promote translocation of the amino-terminal light chain across the vesicle membrane (4) and into the cytosol (5).
  • As shown on this and the next slide, the targets for the botulinum neurotoxins are proteins involved in fusion of acetylcholine vesicles at the presynaptic membrane. Vesicle fusion requires the interaction of VAMP (vesicle-associated membrane protein), SNAP-25 (25 kDa synaptosome-associated protein), and syntaxin, among other proteins, to form the SNARE (SNAP receptor) complex.
  • Each neurotoxin has a unique site of cleavage. Both BTX-A and BTX-E cleave the C-terminus of SNAP-25. However, BTX-A removes nine amino acids, while E removes 26 residues. This difference has significant consequences for the duration of action--the clinical effect of A lasts up to four months, while the effects of E fade within two weeks. There is still controversy whether the extended action of A is due to persistence of catalytic activity or prolonged blocking action by the cleaved SNAP-25. On the one hand, cleaved SNAP-25 has been shown to remain associated with syntaxin for prolonged periods, suggesting it plays a continuing role in blocking vesicle fusion (Raciborska, 1999). On the other hand, when A-treated cells are treated with E (to deplete the A-cleaved SNAP-25), there is a gradual return of the A-cleaved fragment, suggesting peristence of the active toxin (Keller, poster presentation; www.toxin99.org). Slide data courtesy of Dr. Ray Stevens, The Scripps Research Institute and Institute for Childhood and Neglected Diseases.
  • The very long duration of effect of BTX-A results in formation of temporary sprouts that substitute for the paralyzed nerve terminal. Sprout formation appears to correlate with the wearing off of clincal effect. A longer-term reinnervation of the parent terminal occurs eventually, with dying back of the sprouts (dePaiva et al. PNAS 1999, 96:3200-3205)
  • The Spasticity Slide Set Faculty Henry Chambers, MD Pediatric Orthopedic and Scoliosis Center San Diego, California Jean-Michel Gracies, MD, PhD Mount Sinai School of Medicine New York, New York Judy Leach, PT WE MOVE New York, New York Patricia Nance, MD Veterans Administration Healthcare Center at Long Beach Long Beach, California Christopher O'Brien, MD Elan Pharmaceuticals San Francisco, California Lauren Seeberger, MD Colorado Neurological Institute Englewood, Colorado David Simpson, MD Mount Sinai School of Medicine New York, New York
  • The Spasticity Slide Set Faculty Henry Chambers, MD Pediatric Orthopedic and Scoliosis Center San Diego, California Jean-Michel Gracies, MD, PhD Mount Sinai School of Medicine New York, New York Judy Leach, PT WE MOVE New York, New York Patricia Nance, MD Veterans Administration Healthcare Center at Long Beach Long Beach, California Christopher O'Brien, MD Elan Pharmaceuticals San Francisco, California Lauren Seeberger, MD Colorado Neurological Institute Englewood, Colorado David Simpson, MD Mount Sinai School of Medicine New York, New York
  • Botulinum Toxin: Mechanism of Action

    1. 1. Botulinum Toxin: Mechanism of Action Part 1 of 1
    2. 2. Botulinum Neurotoxin Side View
    3. 3. Clostridium botulinum neurotoxin Type B
    4. 4. Binding and Internalization
    5. 5. Ach Vesicle Fusion Complex
    6. 6. Botulinum Toxin Cleavage Targets
    7. 7. Reinnervation
    8. 8. The Spasticity Slide Set Faculty <ul><li>Henry G. Chambers, MD Children's Hospital and Health Center San Diego, California </li></ul><ul><li>Jean-Michel Gracies, MD, PhD Assistant Professor of Neurology Mount Sinai School of Medicine New York, New York </li></ul><ul><li>Judy Leach, P.T. Physical Therapy Consultant San Diego, CA </li></ul><ul><li>Patricia Nance, MD, FRCPC Associate Professor in Residence University of California Irvine Orange, CA </li></ul><ul><li>Lauren Seeberger, MD Medical Co-Director, Movement Disorder Center Colorado Neurological Institute Englewood, Colorado </li></ul><ul><li>Chris O'Brien, MD Vice President Medical Affairs Elan Pharmaceuticals South San Francisco, CA </li></ul><ul><li>David M.Simpson, MD Associate Professor of Neurology Director, Clinical Neurophysiology Mount Sinai School of Medicine New York, New York </li></ul>Spasticity Slide Library Version 2.1 - Updated July, 2001
    9. 9. Original Contributing Authors <ul><li>Kathleen Albany, P.T., M.P.H. Physical Therapy Consultant Mahwah, NJ </li></ul><ul><li>Judith Blazer, M.S. Executive Director, WE MOVE New York, NY </li></ul><ul><li>Mitchell F. Brin, M.D. Past-President and Founder, WE MOVE Professor, Department of Neurology Mount Sinai Medical Center New York, NY </li></ul><ul><li>Tom Cava, M.D. Director Rehab, “PC-Rehab” West Orange, NJ </li></ul><ul><li>W. Zev Rymer, M.D. Rehab Institute of Chicago Chicago, IL </li></ul><ul><li>Saud Sadiq, M.D. Department of Neurology St. Luke's Roosevelt Medical Center New York, NY </li></ul><ul><li>Karen Wauters, O.T. Kessler Rehabilitation Center East Orange, NJ </li></ul>Originally produced and distributed by WE MOVE 1999

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