The Nicotinic Acetylcholine Receptor

This system has attracted enormous attention over recent years. Stimulation of the presynaptic membrane of a neuron results in the release of acetylcholine which then diffuses across the synapse. Binding occurs on the receptor (AchR) located in the postsynaptic membrane, producing the opening of an ion 

This receptor system is particularly important for the sensor specialist since it fulfils both the applicational criteria specified above, that is, it could be utilized directly, and it offers promise as a role model for selective sensing technology. 

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Curare is a generic term for various South American arrow poisons. Curare has been used for centuries by the Indians along the Amazon and Orinoco rivers for immobilizing and paralyzing wild animals used for food. Preparations of curare are derived from Strychnos species, which contain quaternary neuromuscular alkaloids like tubocurarine. Tubocurarine is a potent antagonist at the nicotinic acetylcholine receptor. 

Karlin A (2002) Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci 3 102-114... 

Unwin N (2003) Structure and action of the nicotinic acetylcholine receptor explored by electron microscopy. FEES Lett 555 91-95... 

The open channel has in most cases a selective permeability, allowing a restricted class of ions to flow,for example Na+, K+, Ca++ or Cl- and, accordingly, these channels are called Na+-channels, K+-channels, Ca -channels and Cr-channels. In contrast, cation-permeable channels with little selectivity reject all anions but discriminate little among small cations. Little is known about the structures and functions of these non-selective cation channels [1], and so far only one of them, the nicotinic acetylcholine receptor (nAChR, see Nicotinic Receptors), has been characterized in depth [2, 3]. The nAChR is a ligand-gated channel (see below) that does not select well among cations the channel is even permeable to choline, glycine ethylester and tris buffer cations. A number of other plasma... 

Non-selective Cation Channels. Figure 1 The nicotinic acetylcholine receptor (nAChR) is localized within the cell membrane above the cell membrane is the synaptic cleft, below the cytoplasm. Drawing of the closed (left) and open (right) nAChR showing acetylcholine (ACh) binding and cation movement. Dimensions of the receptor were taken from references [2, 3]. 

The AMPA receptors for glutamate, the nicotinic acetylcholine receptor and the 5-HT3-receptor for serotonin are cation channels (Table 1). When they open, the major consequence is a sudden entry of Na+, depolarization and an excitatory postsynaptic potential (EPSP Fig. 1). 

Changeux, JP (1990) The nicotinic acetylcholine receptor an allosteric protein protot5q)e of ligand-gated ion channels. Trends Pharmacol. Sci. 11 485M92. 

Haring, R., and Kloog, Y. Multiple binding sites for phencyclidine on the nicotinic acetylcholine receptor from Torpedo ocel -lata electric organ. I ife Sci 34 1047-1055, 1984. 

Galantamine is a ChE inhibitor, which elevates acetylcholine in the cerebral cortex by slowing the degradation of acetylcholine.37 It also modulates the nicotinic acetylcholine receptors to increase acetylcholine from surviving presynaptic nerve terminals. In addition, it may increase glutamate and serotonin levels. The clinical benefit of action of these additional neurotransmitters is unknown. 

Fig. 6.25 The nicotinic acetylcholine receptor in a membrane. The deciphering of the structure is based on X-ray diffraction and electron microscopy. (According to Kistler and coworkers)...

Another complication is receptor desensitization. Desensitization of the nicotinic acetylcholine receptor is attributed to the receptor, especially in its activated form, changing spontaneously to a desensitized, inactive state. The following is a scheme incorporating all possible desensitized states of the receptor ... 

Unwin, N., Projection structure of the nicotinic acetylcholine receptor distinct conformations of the alpha subunits, J. Mol. Biol., 257, 586-596, 1996. 

Le Novere, N., Changeux, J.P. Molecular evolution of the nicotinic acetylcholine receptor an example of multigene family in excitable cells. J. Mol. Evol. 40 155, 1995. 

Huganir, R.L., Delcour, A.H., Greengard, P., Hess, G.P. Phosphorylation of the nicotinic acetylcholine receptor regulates its rate of desensitization. Nature. 321 774, 1986. 

Ochoa, E., Chattopadhyay, A., McNamee, M. Desensitization of the nicotinic acetylcholine receptor Molecular mechanisms and effect of modulators. Cell Mol. Neurobiol. 9 141, 1989. 

Feng, Y., Niu, T., Xing, H. et al. A common haplotype of the nicotine acetylcholine receptor a4 subunit gene is associated with vulnerability to nicotine addiction in men. Am. J. Hum. Genet. 75 112, 2004. 

Huginir, R.L. and Miles, K. (1989) Functional modulation of the nicotinic acetylcholine receptors. Critical Reviews of Biochemical and Molecular Biology 24, 183-215. 

Some quinolizine derivatives are employed as drugs. One of them is flumequine 280, a member of the quinolone family of antibacterial agents. Cytisine 9 is a ligand of the nicotinic acetylcholine receptor that acts primarily as a cholinomimetic at the ganglionar level, being used as a respiratory stimulant in some countries. Cytisine analogues with improved ability to cross the blood-brain barrier have also been developed <1999FA438>. 

The nicotinic acetylcholine receptor (nAChR) was the first characterized neurotransmitter receptor 197... 

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