Acetylcholine receptors structure

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... 

Stroud, R. M., and J. Tinner-Moore, Acetylcholine receptor, structure, formation and evolution, Ann. Rev. Cell Biol., 1, 317 (1985). 

J. Lindstrom (1986). Acetylcholine receptors structure, function, synthesis, destruction and antigenicity. In A. G. Engel, B. Q. Banker (Eds.). Myology. New York McGraw-Hill, pp. 769-790. 

GABAa Receptor Structure-Function Studies A Reexamination in Light of New Acetylcholine Receptor Structures Myles H. Akabas... 

Wess, J. (1993) Mutational analysis of muscarinic acetylcholine receptors structural basis of ligand/receptor/G protein interactions. Ufe Sci 53 1447-1463. 

Wess J, Blin N, Mutschler E, et al. Muscarinic acetylcholine receptors structural basis of ligand binding and G protein coupling. Life Sci 1995 56 915-922. 

T0nder JE, Olesen PH (2001) Agonists at the a4P2 nicotinic acetylcholine receptors structure-activity relationships and molecular modelling. Curr Med Chem 8 651-674... 

Brisson, A., Unwin, RN.T. Quaternary structure of the acetylcholine receptor. Nature 315 474-477, 1985. 

Muscarinic acetylcholine receptors (mAChRs) form a class of cell surface receptors that are activated upon binding of the neurotransmitter, acetylcholine. Structurally and functionally, mAChRs are prototypical members of the superfamily of G protein-coupled receptors. Following acetylcholine binding, the activated mAChRs interact with distinct classes of heterotrimeric G proteins resulting in the activation or inhibition of distinct downstream signaling cascades. 

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. 

Neurotoxins present in sea snake venoms are summarized. All sea snake venoms are extremely toxic, with low LD5Q values. Most sea snake neurotoxins consist of only 60-62 amino acid residues with 4 disulOde bonds, while some consist of 70 amino acids with 5 disulfide bonds. The origin of toxicity is due to the attachment of 2 neurotoxin molecules to 2 a subunits of an acetylcholine receptor that is composed of a2 6 subunits. The complete structure of several of the sea snake neurotoxins have been worked out. Through chemical modification studies the invariant tryptophan and tyrosine residues of post-synaptic neurotoxins were shown to be of a critical nature to the toxicity function of the molecule. Lysine and arginine are also believed to be important. Other marine vertebrate venoms are not well known. 

In order to understand the exact mechanism of the neurotoxic action, it is important to know the secondary structure of the neurotoxins as well. It is now known that postsynaptic neurotoxins attach to the a-subunits of acetylcholine receptor (AChR). 

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. 

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.

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. 

Matsuyama, T., Luiten, P.G.M., Spencer, J. and Strosberg, A.D. (1988) Ultra-structural localisation of immunoreactive sites for muscarinic acetylcholine receptor proteins in the rat cerebral cortex. Neuroscience Research Communications 2, 69-76. 

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). 

Xu et al. [5] described the effect of (z>)-penicillamine on the binding of several antiacetylcholine receptor monoclonal antibodies to the Torpedo acetylcholine receptor. Penicillamine is covalently incorporated into the acetylcholine receptor through SS exchange at the cysteine residues of the a-subunit, altering the antigenic structure of the receptor. This effect on the structure of the native receptor at the neuromuscular junction may be responsible for the establishment of the autoimmune response to the acetylcholine receptor in (i))-penicillamine-induced myasthenia gravis. Cysteine and penicillamine interact to form penicillamine-cysteine mixed disulfide complexes [6] ... 

The basic reactions of thiolsulfonates have been known for sometime (Field et al., 1961, 1964), but more recently, they have been applied to the study of protein interactions by site-directed modification of native cysteines or through modification of cysteines introduced at particular points in proteins by mutagenesis. Such studies have yielded insights into the structure and binding site characteristics of proteins (Kirley, 1989). Pascual et al. (1998) used AEAETS to probe the acetylcholine receptor from the extracellular side of the membrane in order to investigate the molecular accessibility and electrostatic potential within the open and closed channel. 

Acetylcholine receptors have been classified into subtypes based on early studies of pharmacologic selectivity 186 The intrinsic complexity and the multiplicity of cholinergic receptors became evident upon elucidation of their primary structures 189... 

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