Trends in Biochemical Sciences
Research updateNicotinic receptors in wonderland
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)
- et al.
Allosteric mechanisms in normal and pathological nicotinic acetylcholine receptors
Curr. Opin. Neurobiol.
(2001) On the nature of allosteric transitions: a plausible model
J. Mol. Biol.
(1965)Distance between the agonist and noncompetitive inhibitor sites on the nicotinic acetylcholine receptor
J. Biol. Chem.
(1989)- et al.
Nicotinic receptors in the development and modulation of CNS synapses
Neuron
(1996) Image analysis of the heavy form of the acetylcholine receptor from Torpedo marmorata
J. Mol. Biol.
(1984)Expression and circular dichroism studies of the extracellular domain of the α subunit of the nicotinic acetylcholine receptor
J. Biol. Chem.
(1997)Ligand binding and structural properties of segments of GABAA receptor α 1 subunit overexpressed in Escherichia coli
J. Biol. Chem.
(2000)Improved secondary structure predictions for a nicotinic receptor subunit: incorporation of solvent accessibility and experimental data into a two-dimensional representation
Biophys. J.
(1999)Probing the structure of the nicotinic acetylcholine receptor with 4-benzoylbenzoylcholine, a novel photoaffinity competitive antagonist
J. Biol. Chem.
(2000)Conserved tyrosines in the α subunit of the nicotinic acetylcholine receptor stabilize quaternary ammonium groups of agonists and curariform antagonists
J. Biol. Chem.
(1994)
Crosslinking of α-bungarotoxin to the acetylcholine receptor from Torpedo marmorata by ultraviolet light irradiation
FEBS Lett.
Identification of a novel amino acid α-tyrosine 93 within the active site of the acetylcholine receptor by photoaffinity labeling. Additional evidence for a three-loop model of the acetylcholine binding site
J. Biol. Chem.
Identification of the α subunit half-cystine specifically labeled by an affinity reagent for the acetylcholine receptor binding site
J. Biol. Chem.
An analog of lophotoxin reacts covalently with Tyr190 in the α-subunit of the nicotinic acetylcholine receptor
J. Biol. Chem.
Identification of amino acids contributing to high and low affinity d-tubocurarine sites in the Torpedo nicotinic acetylcholine receptor
J. Biol. Chem.
Identification of equivalent residues in the γ, δ, and ε subunits of the nicotinic receptor that contribute to α-bungarotoxin binding
J. Biol. Chem.
Structure of the nicotinic receptor acetylcholine-binding site. Identification of acidic residues in the δ subunit within 0.9 nm of the α subunit-binding site disulfide
J. Biol. Chem.
Mapping the agonist binding site of the nicotinic acetylcholine receptor. Orientation requirements for activation by covalent agonist
J. Biol. Chem.
RASMOL: biomolecular graphics for all
Trends Biochem. Sci.
Cited by (155)
Structural and functional computational analysis of nicotine analogs as potential neuroprotective compounds in Parkinson disease
2020, Computational Biology and ChemistryInsecticidal efficacy of three benzoate derivatives against Aphis gossypii and its predator Chrysoperla carnea
2019, Ecotoxicology and Environmental SafetyFoccα6, a truncated nAChR subunit, positively correlates with spinosad resistance in the western flower thrips, Frankliniella occidentalis (Pergande)
2018, Insect Biochemistry and Molecular BiologyCitation Excerpt :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).
Cycloxaprid: A novel cis-nitromethylene neonicotinoid insecticide to control imidacloprid-resistant cotton aphid (Aphis gossypii)
2016, Pesticide Biochemistry and PhysiologyThe global status of insect resistance to neonicotinoid insecticides
2015, Pesticide Biochemistry and Physiology