Nicotinic receptor structure

Changeux, JP, Bertrand, D, Corringer, PJ, Dehoene, S, Edelstein, S, Leno, C, Novere, N le, Marubio, L, Picciotto, M and Zoli, M (1998) Brain nicotinic receptors structure and regulation, role in learning and reinforcement. Brain Res. Rev. 26 198-216. 

Romanelli MN, Gratteri P, Guandalini L, Martini E, Bonaccini C, et al. 2007. Central nicotinic receptors Structure, function, ligands, and therapeutic potential. Chem-MedChem 2 746-767. 

Romanelli, M. N., Gratteri, P, GuandaUni, L., Martini, E., Bonaccini, C., Gualtieri, E Central nicotinic receptors structure, function, ligands, and therapeutic potential. Chem. Med. Chem. 2007,2, 746-767. 

Dukat, M., Flammia, D.D., Damaj, M.I., Martin, B., Glennon, R.A., 1999b. Lobeline a nicotine receptor structure-affinity study. Abstracts, College on Problems of Drug Dependence meeting, Acapulco, Mexico, June 12-17, 1999, p. 37. 

The neurotransmitter acetylcholine (ACh) exerts its diverse pharmacological actions via binding to and subsequent activation of two general classes of cell surface receptors, the nicotinic and the mAChRs. These two classes of ACh receptors have distinct structural and functional properties. The nicotinic receptors,... 

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... 

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... 

Just a year after Stephenson s classical paper of 1956, J. del Castillo and B. Katz published an electrophysiological study of the interactions that occurred when pairs of agonists with related structures were applied simultaneously to the nicotinic receptors at the endplate region of skeletal muscle. Their findings could be best explained in terms of a model for receptor activation that has already been briefly introduced in Section 1.2.3 (see particularly Eq. (1.7)). In this scheme, the occupied receptor can isomerize between an active and an inactive state. This is very different from the classical model of Hill, Clark, and Gaddum in which no clear distinction was made between the occupation and activation of a receptor by an agonist. 

Brejc, K., van Dijk, W. J., Klassen, R. V., Schuurmans, M., van der Oost, J., Smit, A. B., and Sixma, T. K., Crystal structures of an ACh-binding protein reveal the ligand-binding domain of nicotinic receptors, Nature, 411, 269-276, 2001. 

Fig. 21.12. Schematic diagram of the putative structure of a levamisole nicotinic receptor. (A)...

FIGURE 11-3 Structure of compounds important to the classification of receptor subtypes at cholinergic synapses. Compounds are subdivided as nicotinic (N) and muscarinic (Ad). The compounds interacting with nicotinic receptors are subdivided further according to whether they are neuromuscular (N,) or ganglionic (N2). Compounds with muscarinic subtype selectivity (M M2, M3, M4) are also noted. 

The intrinsic complexity and the multiplicity of cholinergic receptors became evident upon elucidation of their primary structures. In the CNS, at least nine different sequences of a subunits and three different sequences of (3 subunits of the nicotinic receptor have been identified [10, 11]. Expression of the cloned genes encoding certain subunit combinations yields functional receptors with different sensitivities toward various toxins and agonists. 

Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Dost J, et al. 2001. Crystal structure of an Ach-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411 269. 

Sine SM, Wang HL, Bren NH. 2002. Lysine scanning mutagenesis delinates structural model of the nicotinic receptor ligand binding domain. J Biol Chem 277 29210-292... 

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

Nicotinic receptors are of the ionotropic type which, on stimulation by acetylcholine, nicotine or related agonists, open to allow the passage of sodium ions into the neuron. There are structural differences between the peripheral and neuronal receptors, the former being pentamers composed of two alpha and one beta, gamma and delta sub-units while the latter consist of single alpha and beta sub-units. It is now known that there are at least four variants of the alpha and two of the beta sub-units in the brain. In Alzheimer s disease it would appear that there is a selective reduction in the nicotinic receptors which contain the alpha 3 and 4 sub-units (Figure 2.9). 

Many receptors for neurotransmitters function as ligand-gated channels for Na and/or Ca " ions (see p. 354). The ones that have been studied in the greatest detail are the nicotinic receptors for acetylcholine (see p. 352). These consist of five separate but structurally closely related subunits. Each forms four transmembrane helices, the second of which is involved in the central pore in each case. The type of monomer and its arrangement in the complex is not identical in all receptors of this type. In the neuromuscular junction (see p. 334), the arrangement aPya8 is found (1). 

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