Nicotinic acetylcholine receptors composition

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. 

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.

That UNCL was found to target to the NE was surprising because it was uncovered in a study to identify chaperones that function in assembly of nicotinic acetylcholine receptors (Fitzgerald et al. 2000). Although little note was taken of the fact at the time, its discovery provided the first indication that NET composition differs among different cell types the study was predicated on the observation that these receptors do not properly assemble in many mammalian cell lines and, indeed, UNCL is absent from most cell types. 

One of the structurally and otherwise best known complex receptors is the nicotinic acetylcholine receptor (nAChR). The nAChR functions as a neurotransmitter in higher organisms. It is the most completely characterized neurotransmitter and ion channel. More than 20 acetylcholine receptor subunits have been cloned from different species. The monomeric receptor protein, functioning as a non-specific ion channel, consists of five subunits composed of a, P, y, and 6 chains. The composition of nAChR has been determined as a2Py6 (62). Several detailed structural models have been constructed for this receptor (63-65). Because of the prominence of the nAChR several concepts are illustrated exploiting this receptor (Section 6.2, Appendix 10). 

Receptors for several neurotransmitters form ion-selective channels in the plasma membrane and diffuse their signals by altering the cell s membrane potential or the cytoplasmic ionic composition. This subfamily of receptors included the well-characterized nicotinic acetylcholine receptor from electric organ, muscle and brain, the receptors for the excitatory amino acids (aspartate and glutamate), the inhibitory amino acids (7-aminobutyrate (GABA), glycine). 

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... 

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... 

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). 

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... 

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