Research update
Nicotinic receptors in wonderland

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Abstract

The structure of a soluble homopentameric homologue of the N-terminal extracellular domain of the nicotinic acetylcholine (ACh) receptor has recently been determined at the atomic level. These data reveal the three-dimensional structure of the binding site for ACh and nicotinic ligands. The ACh-binding sites are located at subunit boundaries in an equatorial position and are framed by residues previously identified in nicotinic receptors, by photoaffinity labelling and mutagenesis experiments, as being crucial for ligand binding. On this basis, a hypothetical mechanism for the allosteric transitions of the nicotinic receptors is suggested.

Section snippets

Molecular structure of nicotinic receptors

The nAChR from fish electric organ is a heteropentamer of ∼300 kDa with an (α1)2.β1.γ/ε.δ stoichiometry. The receptor has two distinct ACh-binding sites (located at interfaces between the α and γ, and the α and δ, subunits), a unique ion channel along the transmembrane axis of (pseudo)symmetry, and all the structural elements that mediate allosteric coupling of the two binding sites during activation and desensitization 4. In response to ACh, single nAChR molecules undergo a conformational

Atomic structure of AChBP, a naturally occurring analogue of the nAChR ligand-binding domain

As discovered by Smit et al.5, AChBP is synthesized in glial cells of snail brain and is released in the synaptic cleft, in an ACh-dependent manner, where it acts as a protein buffer and regulates interneuronal transmission. AChBP shares similar amino acid domains and significant sequence identity with the extracellular parts of the nAChR α subunits (notably ∼24% with α7), and assembles into homopentamers. However, unlike nAChR, AChBP lacks transmembrane domains. Nearly all the residues that

A hypothetical mechanism for the allosteric transitions of nicotinic receptors

With the crystal structure data in hand, the next major issue is to decipher the allosteric mechanism that mediates the activation and desensitization of the nAChR ion channel from a 20–30 Å distant agonist-binding site. The high affinity of AChBP for nicotinic ligands (agonists and antagonists), and Hill coefficients that are either equal or below unity 5, suggest (but do not prove) that AChBP was crystallized in a frozen ‘desensitized’ (D) state. Therefore, one might further hypothesize that

Concluding remarks

The three-dimensional structure at the atomic level of a soluble, homopentameric homologue of the N-terminal extracellular domain of the nAChRs brings an outstanding insight to the knowledge of neurotransmitter receptor mechanisms. The high resolution data pave the way to the elucidation of the still pending enigma of nAChR channel activation and desensitization mechanisms, and are anticipated to facilitate drug design against, for example, nicotine addiction, anxiety, pain, neurodegeneration

Acknowledgements

We thank S.J. Edelstein, P.J. Corringer and N. Le Novère for critical comments and suggestions, N. Le Novère for providing sequence alignment, and A.B. Smit and T.K. Sixma for AChBP coordinates.

References (40)

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    nAChRs exist in the nerve membrane as hetero-pentamers (either two α subunits or various combinations of α or non-α subunits) or homo-pentamers (five α subunits) arranged around a central pore that is permeable to cations (Jones and Sattelle, 2004; Millar and Gotti, 2009). ACh binds to the N-terminal extracellular domain of the subunit, and the binding site is formed by loop A-C of an α subunit and loop D-F of another α or a non-α subunit (Grutter and Changeux, 2001). By definition, α subunits have two adjacent cysteine residues in loop C, and these residues are important for ACh binding (Kao et al., 1984; Kao and Karlin, 1986) whereas non-α subunits (β, δ, ε, or γ) lack these neighboring cysteines (Jones et al., 2010; Sargent, 1993; Sattelle et al., 2005).

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