Nicotinic acetylcholine receptors activation mechanism

Neonicotinoids are potent broad-spectrum insecticides that exhibit contact, stomach and systemic activity. Acetamiprid, imidacloprid, nitenpyram, thiamethoxam and thiacloprid are representatives of the neonicotinoid insecticides (Figure 1). The mechanism of action is similar to that of nicotine, acting on the central nervous system causing irreversible blocking of postsynaptic nicotinic acetylcholine receptors (nAChR). Neonicotinoid insecticides are often categorized as antagonists of the... 

Edmonds, B., Gibb, A. J., and Colquhoun, D., Mechanisms of activation of muscle nicotinic acetylcholine receptors and the time course of endplate currents, Annu. Rev. Physiol., 57, 469-493, 1995. 

Lingle, C. L., Maconochie, D., and Steinbach, J. H., Activation of skeletal muscle nicotinic acetylcholine receptors, J. Memb. Biol., 126, 195-217, 1992 (excellent review of much of the evidence concerning the mechanism of receptor activation). 

Dineley, K.T., Westerman, M., Bui, D., Bell, K., Ashe, K.H., Sweatt, J.D. Beta-amyloid activates the mitogen-activated protein kinase cascade via hippocampal alpha7 nicotinic acetylcholine receptors in vitro and in vivo mechanisms related to Alzheimer s disease. J. Neurosci. 21 4125, 2001. 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

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. 

Two groups of acetylcholine receptors have been identified in humans the muscarinic (mAChR) and nicotinic (nAChR) receptors, named after their artificial activating ligands, muscarine and nicotine. These receptors function through entirely different mechanisms, either as a slow acting metabotropic G-protein-coupled receptor (mAChR) or fast acting ion-channel type receptor (nAChR). 

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