Tyrosine acetylcholine receptors

Neurotoxins present in sea snake venoms are summarized. All sea snake venoms are extremely toxic, with low LD5Q values. Most sea snake neurotoxins consist of only 60-62 amino acid residues with 4 disulOde bonds, while some consist of 70 amino acids with 5 disulfide bonds. The origin of toxicity is due to the attachment of 2 neurotoxin molecules to 2 a subunits of an acetylcholine receptor that is composed of a2 6 subunits. The complete structure of several of the sea snake neurotoxins have been worked out. Through chemical modification studies the invariant tryptophan and tyrosine residues of post-synaptic neurotoxins were shown to be of a critical nature to the toxicity function of the molecule. Lysine and arginine are also believed to be important. Other marine vertebrate venoms are not well known. 

Hopfield, J.F., Tank, D.W., Greengard, P. and Huganir, R.L. (1988) Functional modulation of the nicotinic acetylcholine receptor by tyrosine phosphorylation. Nature 336, 677-680. 

Tyrosine phosphorylation has a role in the formation of the neuromuscular synapse. For instance, the acetylcholine receptor (AChR) is concentrated at the postsynaptic membrane of the neuromuscular junction at a density of 10,000 receptors/pm2, which is about three orders of magnitude higher than that of the extrasynaptic region... 

Meyer, G. and Wallace, B. G. Recruitment of a nicotinic acetylcholine receptor mutant lacking cytoplasmic tyrosine residues in its beta subunit into agrin-induced aggregates. Mol. Cell. Neurosci. 11 324-333,1998. 

Anderson DJ, Puttfarcken PS, Jacobs 1, Faltynek C (2000) Assessment of nicotinic acetylcholine receptor-mediated release of [ H]-norepinephrine from rat brain slices using a new 96-well format assay. Neuropharmacology 39 2663-2672 Anney RJ, Olsson CA, Lotfi-Miri M, Patton GC, Williamson R (2004) Nicotine dependence in a prospective population-based study of adolescents the protective role of a functional tyrosine hydroxylase polymorphism. Pharmacogenetics 14 73-81 Auerbach A, Akk G (1998) Desensitization of mouse nicotinic acetylcholine receptor channels. 

Friese, M. B., Blagden, C. S. and Burden, S. J. (2007) Synaptic differentiation is defective in mice lacking acetylcholine receptor beta-subunit tyrosine phosphorylation. Development 134,4167-4 176. 

Felsch J, Cachero T. 1998. Activation of protein tyrosine kinase Pyk2by the ml muscarinic acetylcholine receptor. Proc Natl Acad Sci USA 95 5051-5056. 

Corfas G, Falls DL, Fischbach GD. 1993. ARIA, a protein that stimulates acetylcholine receptor synthesis, also induces tyrosine phosphorylation of a 185-kDa muscle transmembrane protein. Proc Natl Acad Sci USA 90 1624-1628. 

Semm testing reveals circulating antibodies to acetylcholine receptors in approximately 90% of individuals with generalized myasthenia and in almost 70% of those with ocular symptoms only. False-positive results are rare, and the antibody titer does not correlate with the severity of symptoms. In those patients who are seronegative for antiacetylcholine receptor antibodies, which is about 6% of myasthenia gravis patients overall, anti-MuSK antibodies may be present. MuSK is a muscle-specific transmembrane protein with intrinsic tyrosine kinase activity. Anti-MuSK antibodies are almost never seen in patients who have antiacetylcholine receptor antibodies, and vice versa. 

B. Effectors Effectors are molecules that translate the drug-receptor interaction into a change in cellular activity. The best examples of effectors are enzymes such as adenylyl cyclase. Some receptors are also effectors in that a single molecule may incorporate both the drug binding site and the effector mechanism, eg, the tyrosine kinase effector of the insulin receptor, or the sodium-potassium channel of the nicotinic acetylcholine receptor. 

Huang XY, Morielli AD, Peralta EG. Tyrosine kinase-dependent suppression of a potassium channel by the G protein-coupled ml muscarinic acetylcholine receptor. Cell 1993 75(6) 1145-1156. 

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