Nicotinic receptor composition

Champtiaux, N., Gotti, C., Cordero-Erausquin, M. et al. Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice. J. Neurosci. 23 7820, 2003. 

Champtiaux N, Han ZY, Bessis A, Rossi FM, Zoli M, Marubio L, McIntosh JM, Changeux JP (2002) Distribution and pharmacology of alpha 6-containing nicotinic acetylchohne receptors analyzed with mutant mice, J Neurosci 22 1208-1217 Champtiaux N, Gotti C, Cordero-Erausquin M, David DJ, Przybylski C, Lena C (2003) Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knockout mice, J Neurosci 23 7820-7829... 

Mogg AJ, Jones FA, PuUar lA, Sharpies CG, Wonnacott S (2004) Functional responses and subunit composition of presynaptic nicotinic receptor subtypes explored using the novel agonist 5-iodo-A-85380. Neuropharmacology 47 848-859... 

Quik M, VaUati S, Bordia T, Kulak JM, Fan H, McIntosh JM, Clementi F, Gotti C (2005) Subunit composition of nicotinic receptors in monkey striatum effect of treatments with l-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine or L-DOPA. Mol Pharmacol 67 32-41... 

The interest in neuronal nAChRs has increased in the past few years and a great number of papers were published on the establishment of the physiology of nAChRs including the determination of type, composition, and number of nAChRs present in different tissues, as well as on their pharmacological properties. The need to understand the functional implications of nAChRs in the human brain arises from several known facts, namelly, the reduced number of nAChRs seen in both Alzheimer s and Parkinson s diseases, the importance of cholinergic defects in particular forms of human epilepsy and the decreased number of hippocampal nicotinic receptors seen in postmorten brain tissue of schizophrenia patients. The presence of nAChRs in lung carcinoma cells and the potential role of nicotine in learning and memory was also reported. 

The problem is further compounded by the difficulty of carrying out kinetic studies on neuronal nicotinic receptors (mostly because of rundown) this means, for instance, that we do not know anything about agonist binding affinities or efficacy and how these change with subunit composition (or indeed with inherited mutations). 

Lansdell, SJ. and Millar, N.S. (2000). The influence of nicotinic receptor subunit composition upon agonist, alpha-bungarotoxin and insecticide (rtnida-cloprid) binding affinity. Neuropharmacology 39, 671-679. 

P), 60,000 (56,279) (y) and 65,000 (57,565) (6) (the first value is from SDS the value in brackets is the exact M, based on amino acid composition) in the ratio 2 1 1 1, with an average 40% amino-acid sequence identity between all 4 chains [B.M.Conti-Troconi et al. Science 218 (1982) 1227-1229]. DNA for all 4 subunits has been cloned and sequenced [M. Noda et al. Nature 301 (1983) 251-254]. The covalent affinity probes, [ H]-bromoacetylcholine and 4-(AI-maleiniideo)- H tenzyl trimethylammonium iodide, label the a-subunit by reacting with cysteine residues 192 and 193. Thus, each of ffie two a-subunits carries an acetylcholine binding site, and there are 2 sites per oligomeric receptor. When incorporated into liposomes or planar li bilaye the nicotinic receptor permits a flux of a, which is promoted... 

Fernandes CC, Berg DK, Gomez-Varela D (2010) Lateral mobility of nicotinic acetylcholine receptors on neurons is determined by receptor composition, local domain, and cell type. J Neurosci 30 8841-8851... 

Lthanol (or alcohol) is a two-carbon molecule that, in contrast to many other drugs of abuse, such as opioids, cocaine, and nicotine, does not bind to specific brain receptors. Nonetheless, alcohol affects a variety of neurotransmitter systems, including virtually all of the major systems that have been associated with psychiatric symptoms (Kranzier 1995). Alcohol affects these neurotransmitter systems indirectly by modifying the composition and functioning of... 

Salminen, O., Murphy, K.L., McIntosh, J.M., et al. Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. Mol. Pharmacol. 65 1526, 2004. 

Salminen, O., Whiteaker, P., Grady, S.R., Collins, A.C., McIntosh, J.M., Marks, M.J. The subunit composition and pharmacology of alpha-Conotoxin Mil-binding nicotinic acetylcholine receptors studied by a novel membrane-binding assay. Neuropharmacology. 48 696, 2005. 

Fenster CP, Rains MF, Noerager B, Quick MW, Lester RAJ (1997) Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine. J Neurosci 17 5747-5759... 

Inhaled nicotine is efficiently delivered to the brain (see chapter by Benowitz, this volume) where it selectively interacts with its central targets, the neuronal nicotinic acetylcholine receptors (nAChRs). The multiple subtypes of uAChR (see chapter by Collins et al, this volume) all bind nicotine but with different affinities, depending on the subunit composition of the uAChR. Binding may result in activation or desensitisation of uAChRs, reflecting the temporal characteristics of nicotine dehvery and local concentration of nicotine. Another level of complexity of the actions of nicotine reflects the widespread and non-uniform distribution of uAChR subtypes within the brain, such that nicotine can influence many centrally regulated functions in addition to the reward systems. In this chapter, we address the consequences of nicotine interactions with nAChRs at the molecular, cellular and anatomical levels. We critically evaluate experimental approaches, with respect to their relevance to human smoking, and contrast the acute and chronic effects of nicotine. 

Figure 6. Proposed inner wall structure of the nicotinic acetylcholine receptor-channel composite from a2pY8 subunit assembly. The channel mouth is constructed from charged amino acids and their amides such as Asp, Glu, and Gin. A Lys is located at just the inner mouth. The lower half is covered by the amino acids having hydroxyl such as Ser and Thr, while the upper half is lined up with hydrophobic residues such as Leu, Val, Ala, lie, and Phe.

In the peripheral (Wessler 1989) as well as central (Wonnacott 1997) nervous system, presynaptic nicotinic autoreceptors were reported to control the release of acetylcholine. In both locations, the consequence of presynaptic nAChR activation most commonly is an increase in both spontaneous and evoked acetylcholine release (MacDermott et al. 1999), whereas presynaptic muscarinic receptors mediate the opposite effect, an autoinhibition. Recent studies have focused on the composition of presynaptic nAChRs (Table 2). In the hippocampus, nicotinic autoreceptors were suggested to be a3/p4 receptors (Tani et al. 1998), but a role of p2 subunits has also been implicated (Lloyd et al. 1998). Likewise, in the neocortex, presynaptic nicotinic autoreceptors are likely to be 04/ p2 receptors (Marchi et al. 2002). In contrast, in the interpeduncular nucleus the autoreceptors were suggested to mainly contain a3 and p4 subunits (Grady et al. 2001). 

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