Overview of neuromuscular junction toxins
- Tracy Weimer, MD
Tracy Weimer, MD
- Assistant Professor, Department of Neurology
- West Virginia University School of Medicine
- Laurie Gutmann, MD
Laurie Gutmann, MD
- Professor and Vice Chair of Clinical Research
- University of Iowa
Signal transduction at the neuromuscular junction is a multistep, complex process required for many of the functions that sustain life. Neuromuscular toxins act in various ways to inhibit this process. These toxins are naturally occurring , and some have been developed as biochemical weapons.
This topic will briefly discuss the neuromuscular transmission disorders due to botulism, tick paralysis, snake venom, organophosphates and carbamates, and hypermagnesemia or hypocalcemia.
Acquired myasthenia gravis, congenital and neonatal myasthenia gravis, and Lambert-Eaton myasthenic syndrome are discussed separately. (See "Pathogenesis of myasthenia gravis" and "Clinical manifestations of myasthenia gravis" and "Neuromuscular junction disorders in newborns and infants" and "Clinical features and diagnosis of Lambert-Eaton myasthenic syndrome".)
THE NEUROMUSCULAR JUNCTION
The neuromuscular junction consists of a presynaptic axon terminal and a postsynaptic muscle end plate (figure 1). Within the presynaptic terminal are vesicles containing acetylcholine, adenosine triphosphate (ATP), magnesium, and calcium [2,3]. Most of these vesicles are bound to the actin cytoskeleton by proteins called synapsins. When an action potential induces opening of calcium channels, increased intracellular calcium levels promote phosphorylation of synapsins. This phosphorylation results in release of the vesicles from their cytoskeletal sites .
After release from the cytoskeleton, vesicles become bound at the presynaptic membrane terminal in areas called active zones [2,5]. This "docking" allows rapid exocytosis of the vesicles. Docking is mediated by proteins termed SNARES (soluble N-ethylmaleimide-sensitive-fusion-attachment protein receptors). SNARES attached to the terminal membrane (t-SNARES) form complexes with proteins located on the vesicle (v-SNARES) [6-8].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Senanayake N, Román GC. Disorders of neuromuscular transmission due to natural environmental toxins. J Neurol Sci 1992; 107:1.
- Whittaker VP. The structure and function of cholinergic synaptic vesicles. The Third Thudichum Lecture. Biochem Soc Trans 1984; 12:561.
- Wagner JA, Carlson SS, Kelly RB. Chemical and physical characterization of cholinergic synaptic vesicles. Biochemistry 1978; 17:1199.
- Benfenati F, Valtorta F, Rubenstein JL, et al. Synaptic vesicle-associated Ca2+/calmodulin-dependent protein kinase II is a binding protein for synapsin I. Nature 1992; 359:417.
- Dreyer F, Peper K, Akert K, et al. Ultrastructure of the "active zone" in the frog neuromuscular junction. Brain Res 1973; 62:373.
- Sheng ZH, Westenbroek RE, Catterall WA. Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking/fusion machinery. J Bioenerg Biomembr 1998; 30:335.
- Söllner T, Whiteheart SW, Brunner M, et al. SNAP receptors implicated in vesicle targeting and fusion. Nature 1993; 362:318.
- Schiavo G, Matteoli M, Montecucco C. Neurotoxins affecting neuroexocytosis. Physiol Rev 2000; 80:717.
- Schwartz JH. Chemical messengers: small molecules and peptides. In: Principles of Neural Science, 3rd ed, Kandel ER, Schwartz JH, Jessell TM (Eds), Appleton and Lange, 1991. p.229.
- Dwyer T. The electrochemical basis of nerve function. In: Fundamental Neuroscience for Basic and Clinical Applications, 3rd ed, Haines D (Ed), Elsevier, Singapore 2006. p.41.
- Meriggioli MN, Sanders DB. Advances in the diagnosis of neuromuscular junction disorders. Am J Phys Med Rehabil 2005; 84:627.
- Cherington M. Electrophysiologic methods as an aid in diagnosis of botulism: a review. Muscle Nerve 1982; 5:S28.
- Trontelj JV, Sanders DB, Stalber EV. Electrophysiologic methods for assessing neuromuscular transmission. In: Neuromuscular Function and Disease, Brown WF, Bolton CF, Aminoff MJ (Eds), WB Saunders Company, 2002. p.431.
- Cooper BJ, Spence I. Temperature-dependent inhibition of evoked acetylcholine release in tick paralysis. Nature 1976; 263:693.
- Chand KK, Lee KM, Lavidis NA, et al. Tick holocyclotoxins trigger host paralysis by presynaptic inhibition. Sci Rep 2016; 6:29446.
- Cherington M, Synder RD. Tick paralysis. Neurophysiologic studies. N Engl J Med 1968; 278:95.
- Kimura J. Myasthenia gravis and other disorders of neuromuscular transmission. In: Electrodiagnosis on Diseases of Nerve and Muscle: Principles and Practice, Kimura J (Ed), Oxford University Press, 2001. p.765.
- Mebs D. Venomous and Poisonous Animals: A Handbook for Biologists, Toxicologists and Toxinologists, Physicians and Pharmacists, Medpharm Scientific Publishers CRC Press, Boca Raton 2002. p.239.
- Warrell DA. Snake bite. Lancet 2010; 375:77.
- Kini RM. Venom Phospholipase A2 Enzymes: Structure, Function, and Mechanism, Wiley, Chichester 1997.
- Lewis RL, Gutmann L. Snake venoms and the neuromuscular junction. Semin Neurol 2004; 24:175.
- Karalliedde L. Animal toxins. Br J Anaesth 1995; 74:319.
- Dixon RW, Harris JB. Nerve terminal damage by beta-bungarotoxin: its clinical significance. Am J Pathol 1999; 154:447.
- Connolly S, Trevett AJ, Nwokolo NC, et al. Neuromuscular effects of Papuan Taipan snake venom. Ann Neurol 1995; 38:916.
- Harris JB, Grubb BD, Maltin CA, Dixon R. The neurotoxicity of the venom phospholipases A(2), notexin and taipoxin. Exp Neurol 2000; 161:517.
- Hodgson WC, Wickramaratna JC. In vitro neuromuscular activity of snake venoms. Clin Exp Pharmacol Physiol 2002; 29:807.
- Harris JB, Goonetilleke A. Animal poisons and the nervous system: what the neurologist needs to know. J Neurol Neurosurg Psychiatry 2004; 75 Suppl 3:iii40.
- White J, Warrell D, Eddleston M, et al. Clinical toxinology--where are we now? J Toxicol Clin Toxicol 2003; 41:263.
- Kumar S, Usgaonkar RS. Myasthenia gravis--like picture resulting from snake bite. J Indian Med Assoc 1968; 50:428.
- Brick JF, Gutmann L. Rattlesnake venom-induced myokymia. Muscle Nerve 1982; 5:S98.
- Howard JF Jr. Adverse drug effects on neuromuscular transmission. Semin Neurol 1990; 10:89.
- Sieb JP. Fluoroquinolone antibiotics block neuromuscular transmission. Neurology 1998; 50:804.
- Argov Z, Mastaglia FL. Drug therapy: Disorders of neuromuscular transmission caused by drugs. N Engl J Med 1979; 301:409.
- Argov Z, Wirguin I. Drugs and the neuromuscular junction pharmacotherapy of transmission disorders and drug-induced myasthenic syndromes. In: Handbook of Myasthenia Gravis and Myasthenic Syndromes, Lisak RP (Ed), Marcel Dekker, New York 1994. p.295.
- Wislicki L. Excitatory and depressant effects of beta-adrenoceptor blocking agents on skeletal muscle. Arch Int Pharmacodyn Ther 1969; 182:310.
- Werman R, Wislicki L. Propranolol, a curariform and cholinomimetic agent at the frog neuromuscular junction. Comp Gen Pharmacol 1971; 2:69.
- Vizi ES, Illés P, Rónai A, Knoll J. Effect of lithium on acetylcholine release and synthesis. Neuropharmacology 1972; 11:521.
- Lee P, Tai DY. Clinical features of patients with acute organophosphate poisoning requiring intensive care. Intensive Care Med 2001; 27:694.
- Besser R, Gutmann L, Dillmann U, et al. End-plate dysfunction in acute organophosphate intoxication. Neurology 1989; 39:561.
- Senanayake N, Karalliedde L. Neurotoxic effects of organophosphorus insecticides. An intermediate syndrome. N Engl J Med 1987; 316:761.
- Shnider, SM, Levinson, G. Anesthesia for obstetrics. In: Anesthesia, 4th ed, Churchill Livingstone, New York 1994. p.2031.
- THE NEUROMUSCULAR JUNCTION
- Clinical features
- TICK PARALYSIS
- Clinical features
- SNAKE VENOM
- Clinical features and diagnosis
- Clinical features and diagnosis
- ORGANOPHOSPHATE AND CARBAMATE TOXICITY
- Clinical features
- SUMMARY AND RECOMMENDATIONS