Acetylcholin Receptor, nicotinic Structure

Figure 2.1 Diagram of nicotinic acetylcholine receptor (nAChR) structure. A top view of (A) an a7 nAChR and (B) a p2 nAChR shows that homomeric and heteromeric classes of nAChRs are both pentameric in structure. Each subunit is made up of four transmembrane domains with the M2 domain making up the ion pore. (C) A side view of the four transmembrane regions shows the N terminus, C terminus, and large M3-M4 intracellular loop that make up each nAChR subunit. The extracellular loops are available for binding to ligands and the intracellular loop is available for regulation of the nAChR by intracellular signaling proteins.

Hogg RC, Raggenbass M, Bertrand D (2003) Nicotinic acetylcholine receptors from structure to brain function. Rev Physiol Biochem Pharmacol 147 1 6 Holmes S, Zwar N, Jimenez-Ruiz CA, Ryan PJ, Browning D, Bergmann L, Johnston JA (2004) Bupropion as an aid to smoking cessation a review of real-life effectiveness. Int J Chn Pract 58 285-291... 

Nicotinic Acetylcholine Receptors. Nicotinic acetylcholine receptors are ligandgated ion channels whose opening is controlled by acetylcholine and nicotine agonists (196,209,210). They are transmembrane protein structures. Each receptor consists of five subunits. The structure is inserted in the plasma membrane with an aqueous channel in... 

D. Bertrand, Nicotinic acetylcholine receptors from structure to brain function, Rev. Physiol. Biochem. Pharmacol. 2003, 147,1-46. 

Tobacco is another commonly abused stimulant. It contains nicotine as the major stimulant. As mentioned earlier (Sect. 17.1), our brain has a receptor for nicotine, a part of acetylcholine receptor. Nicotine is an alkaloid and its structure is shown in Fig. 17.2. Tobacco plants produce nicotine as a defense chemical, to kill some insects. Nicotine has indeed been used as an insecticide for long. It is poisonous to human body, too, and a small amount can kill. In smaller quantities (as found in inhaled smoke), it can act as a stimulant interacting with the receptor as mentioned earlier, and it is quite addictive. 

Jensen AA, Frolund B, Liljefors T et al (2005) Neuronal nicotinic acetylcholine receptors structural revelations, target identifications, and therapeutic inspirations. J Med Chem 48 4705—4745... 

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... 

These include nicotinic acetylcholine receptors, neuronal calcium channels, muscle sodium channels, vasopressin receptors, and iV-methyl-D-aspartate (NMDA) receptors. Some general features of the structure, function, and evolution of biologically active peptides isolated from Conus venom are presented. 

Unwin, N (1995) Acetylcholine receptor channel imaged in the open state. Nature 373 37-43. Unwin, N (2000) Nicotinic acetylcholine receptor and the structural basis of fast synaptic transmission. Phil. Trans. Roy. Soc. Lond. Ser. B 355 1813-1829. 

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)...

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

Lindstrom, J.M. Nicotinic acetylcholine receptors of muscles and nerves comparison of their structures, functional roles, and vulnerability to pathology. Ann. N.Y. Acad. Sci. 998 41, 2003. 

Karlin, A., Akabas, M.H. Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron. 15 1231, 1995. 

Karlin A (1993). Structure of nicotine acetylcholine receptors. Current Opinion in Neurobiology, 3, 299-309. 

Cytisine is a tricyclic quinolizidine alkaloid that binds with high affinity and specificity to nicotinic acetylcholine receptors. In principle, this compound can exist in several conformations, but semi-empirical calculations at the AM 1 and PM3 levels have shown that stmctures 19 and 20 are more stable than other possible conformers by more than 50 kcalmol-1. Both structures differ by 3.7 kcalmol 1 at the AMI level and 2.0 kcalmol 1 at the PM3 level, although this difference is much smaller when ab initio calculations are employed <2001PJC1483>. This conclusion is in agreement with infrared (IR) studies and with H NMR data obtained in CDCI3 solution, which are compatible with an exo-endo equilibrium < 1987JP21159>, although in the solid state cytisine has an exo NH proton (stmcture 19) (see Section 12.01.3.4.2). 

Acetylcholine receptors have been classified into sub-types based on early studies of pharmacologic selectivity. Long before structures were known, two crude alkaloid fractions, containing nicotine and muscarine (Fig. 11-2), were used to subclassify receptors in the cholinergic nervous system (Fig. 11-3). The greatly different... 

Karlin, A. Emerging structures of nicotinic acetylcholine receptors. Nat. Rev. Neurosci. 3,102-114, 2002. 

Albuquerque EX, Aracava Y, Cintra WM, Brossi A, Schonenberger B, Deshpande SS. Structure-activity relationship of reversible cholinesterase inhibitors activation, channel blockade and stereospecificity of the nicotinic acetylcholine receptor-ion channel complex. Braz. J. Med. Biol. Res. 21 1173-1196, 1988. 

Hucho, F., Gorne-Tschelnokow, U., and Strecker, A. (1994). /3-structure in the membrane-spanning part of the nicotinic acetylcholine receptor (or how helical are transmem-brane helices ). Trends Biochem. Sci. 19, 383—387. 

Structure of fluorescent probes that have been used to study ligand binding to the Torpedo nicotinic acetylcholine receptor... 

Cohen JB, Sharp SD, Liu WS. 1991. Structure of the agonistbinding site of the nicotinic acetylcholine receptor. [ H] acetylcholine mustard identified residues in the cation binding subsite. J Biol Chem 266 23354-23364. 

Sullivan D, Chiara DC, Cohen JB. 2002. Mapping the agonist binding site of the nicotinic acetylcholine receptor by cysteine scanning mutagenesis antagonist footprint and secondary structure predictions. Mol Pharmacol 61 ... 

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