Abstract
Lipids are potent modulators of the Torpedo nicotinic acetylcholine receptor. Lipids influence nicotinic receptor function by allosteric mechanisms, stabilizing varying proportions of pre-existing resting, open, desensitized, and uncoupled conformations. Recent structures reveal that lipids could alter function by modulating transmembrane α-helix/α-helix packing, which in turn could alter the conformation of the allosteric interface that links the agonist-binding and transmembrane pore domains—this interface is essential in the coupling of agonist binding to channel gating. We discuss potential mechanisms by which lipids stabilize different conformational states in the context of the hypothesis that lipid–nicotinic receptor interactions modulate receptor function at biological synapses.
Similar content being viewed by others
Abbreviations
- ABD:
-
Agonist binding domain
- nAChR:
-
Nicotinic acetylcholine receptor
- ELIC:
-
Erwinia ligand-gated ion channel
- GLIC:
-
Gloebacter ligand-gated ion channel
- PA:
-
Phosphatidic acid
- TMD:
-
Transmembrane domain
References
Addona GH, Sandermann H Jr, Kloczewiak MA, Husain SS, Miller KW (1998) Where does cholesterol act during activation of the nicotinic acetylcholine receptor? Biochim Biophys Acta 1370(2):299–309
Antollini SS, Xu Y, Jiang H, Barrantes FJ (2005) Fluorescence and molecular dynamics studies of the acetylcholine receptor gammaM4 transmembrane peptide in reconstituted systems. Mol Membr Biol 22(6):471–483
Baenziger JE, Morris ML, Darsaut TE, Ryan SE (2000) Effect of membrane lipid composition on the conformational equilibria of the nicotinic acetylcholine receptor. J Biol Chem 275(2):777–784
Baier CJ, Barrantes FJ (2007) Sphingolipids are necessary for nicotinic acetylcholine receptor export in the early secretory pathway. J Neurochem 101(4):1072–1084
Baier CJ, Gallegos CE, Levi V, Barrantes FJ (2010) Cholesterol modulation of nicotinic acetylcholine receptor surface mobility. Eur Biophys J 39(2):213–227. doi:10.1007/s00249-009-0521-2
Blanton MP, Cohen JB (1992) Mapping the lipid-exposed regions in the Torpedo californica nicotinic acetylcholine receptor [published erratum appears in Biochemistry 1992 Jun 30;31(25):5951]. Biochemistry 31(15):3738–3750
Blanton MP, Cohen JB (1994) Identifying the lipid-protein interface of the Torpedo nicotinic acetylcholine receptor: secondary structure implications. Biochemistry 33(10):2859–2872
Blanton MP, Xie Y, Dangott LJ, Cohen JB (1999) The steroid promegestone is a noncompetitive antagonist of the Torpedo nicotinic acetylcholine receptor that interacts with the lipid-protein interface. Mol Pharmacol 55(2):269–278
Bocquet N, Nury H, Baaden M, Le Poupon C, Changeux JP, Delarue M, Corringer PJ (2009) X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457(7225):111–114
Borroni V, Barrantes FJ (2011) Cholesterol modulates the rate and mechanism of acetylcholine receptor internalization. J Biol Chem 286(19):17122–17132
Borroni V, Baier CJ, Lang T, Bonini I, White MM, Garbus I, Barrantes FJ (2007) Cholesterol depletion activates rapid internalization of submicron-sized acetylcholine receptor domains at the cell membrane. Mol Membr Biol 24(1):1–15
Bouzat C, Roccamo AM, Garbus I, Barrantes FJ (1998) Mutations at lipid-exposed residues of the acetylcholine receptor affect its gating kinetics. Mol Pharmacol 54(1):146–153
Bouzat C, Gumilar F, Spitzmaul G, Wang HL, Rayes D, Hansen SB, Taylor P, Sine SM (2004) Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel. Nature 430(7002):896–900
Brannigan G, Henin J, Law R, Eckenhoff R, Klein ML (2008) Embedded cholesterol in the nicotinic acetylcholine receptor. Proc Natl Acad Sci USA 105(38):14418–14423
Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB, Sixma TK (2001) Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411(6835):269–276
Broadbent S, Groot-Kormelink PJ, Krashia PA, Harkness PC, Millar NS, Beato M, Sivilotti LG (2006) Incorporation of the beta3 subunit has a dominant-negative effect on the function of recombinant central-type neuronal nicotinic receptors. Mol Pharmacol 70(4):1350–1357
Bruses JL, Chauvet N, Rutishauser U (2001) Membrane lipid rafts are necessary for the maintenance of the (alpha)7 nicotinic acetylcholine receptor in somatic spines of ciliary neurons. J Neurosci 21(2):504–512
Celie PH, van Rossum-Fikkert SE, van Dijk WJ, Brejc K, Smit AB, Sixma TK (2004) Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41(6):907–914
Criado M, Eibl H, Barrantes FJ (1984) Functional properties of the acetylcholine receptor incorporated in model lipid membranes. Differential effects of chain length and head group of phospholipids on receptor affinity states and receptor-mediated ion translocation. J Biol Chem 259(14):9188–9198
daCosta CJ, Baenziger JE (2009) A lipid-dependent uncoupled conformation of the acetylcholine receptor. J Biol Chem 284(26):17819–17825
daCosta CJ, Ogrel AA, McCardy EA, Blanton MP, Baenziger JE (2002) Lipid-protein interactions at the nicotinic acetylcholine receptor. A functional coupling between nicotinic receptors and phosphatidic acid-containing lipid bilayers. J Biol Chem 277(1):201–208
daCosta CJ, Wagg ID, McKay ME, Baenziger JE (2004) phosphatidic acid and phosphatidylserine have distinct structural and functional interactions with the nicotinic acetylcholine receptor. J Biol Chem 279(15):14967–14974
daCosta CJ, Medaglia SA, Lavigne N, Wang S, Carswell CL, Baenziger JE (2009) Anionic lipids allosterically modulate multiple nicotinic acetylcholine receptor conformational equilibria. J Biol Chem 284(49):33841–33849
Dellisanti CD, Yao Y, Stroud JC, Wang ZZ, Chen L (2007) Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution. Nat Neurosci 10(8):953–962
Drenan RM, Nashmi R, Imoukhuede P, Just H, McKinney S, Lester HA (2008) Subcellular trafficking, pentameric assembly, and subunit stoichiometry of neuronal nicotinic acetylcholine receptors containing fluorescently labeled alpha6 and beta3 subunits. Mol Pharmacol 73(1):27–41
Ellena JF, Blazing MA, McNamee MG (1983) Lipid-protein interactions in reconstituted membranes containing acetylcholine receptor. Biochemistry 22(24):5523–5535
Epstein M, Racker E (1978) Reconstitution of carbamylcholine-dependent sodium ion flux and desensitization of the acetylcholine receptor from Torpedo californica. J Biol Chem 253(19):6660–6662
Fong TM, McNamee MG (1987) Stabilization of acetylcholine receptor secondary structure by cholesterol and negatively charged phospholipids in membranes. Biochemistry 26(13):3871–3880
Gallegos CE, Pediconi MF, Barrantes FJ (2008) Ceramides modulate cell-surface acetylcholine receptor levels. Biochim Biophys Acta 1778(4):917–930
Hamouda AK, Chiara DC, Sauls D, Cohen JB, Blanton MP (2006a) Cholesterol Interacts with Transmembrane alpha-Helices M1, M3, and M4 of the Torpedo Nicotinic Acetylcholine Receptor: Photolabeling Studies Using [(3)H]Azicholesterol. Biochemistry 45(3):976–986
Hamouda AK, Sanghvi M, Sauls D, Machu TK, Blanton MP (2006b) Assessing the lipid requirements of the Torpedo californica nicotinic acetylcholine receptor. Biochemistry 45(13):4327–4337
Hansen SB, Sulzenbacher G, Huxford T, Marchot P, Taylor P, Bourne Y (2005) Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J 24(20):3635–3646
Hansen SB, Tao X, MacKinnon R (2011) Structural basis of PIP2 activation of the classical inward rectifier K + channel Kir2.2. Nature 477(7365):495–498
Heidmann T, Sobel A, Popot JL, Changeux JP (1980) Reconstitution of a functional acetylcholine receptor. Conservation of the conformational and allosteric transitions and recovery of the permeability response; role of lipids. Eur J Biochem 110(1):35–55
Hibbs RE, Gouaux E (2011) Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474(7349):54–60
Hilf RJ, Dutzler R (2008) X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452(7185):375–379
Hilf RJ, Dutzler R (2009) Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457(7225):115–118
Jones OT, McNamee MG (1988) Annular and nonannular binding sites for cholesterol associated with the nicotinic acetylcholine receptor. Biochemistry 27(7):2364–2374
Labriola JM, daCosta CJ, Wang S, Figeys D, Smith JC, Sturgeon RM, Baenziger JE (2010) Phospholipase C activity affinity purifies with the Torpedo nicotinic acetylcholine receptor. J Biol Chem 285(14):10337–10343
Lasalde JA, Tamamizu S, Butler DH, Vibat CR, Hung B, McNamee MG (1996) Tryptophan substitutions at the lipid-exposed transmembrane segment M4 of Torpedo californica acetylcholine receptor govern channel gating. Biochemistry 35(45):14139–14148
Lee AG (2004) How lipids affect the activities of integral membrane proteins. Biochim Biophys Acta 1666(1–2):62–87
Lee YH, Li L, Lasalde J, Rojas L, McNamee M, Ortiz-Miranda SI, Pappone P (1994) Mutations in the M4 domain of Torpedo californica acetylcholine receptor dramatically alter ion channel function. Biophys J 66(3 Pt 1):646–653
Li P, Steinbach JH (2010) The neuronal nicotinic alpha4beta2 receptor has a high maximal probability of being open. Br J Pharmacol 160(8):1906–1915
Li L, Lee YH, Pappone P, Palma A, McNamee MG (1992) Site-specific mutations of nicotinic acetylcholine receptor at the lipid-protein interface dramatically alter ion channel gating. Biophys J 62(1):61–63
Li SX, Huang S, Bren N, Noridomi K, Dellisanti CD, Sine SM, Chen L (2011) Ligand-binding domain of an alpha7-nicotinic receptor chimera and its complex with agonist. Nat Neurosci 14(10):1253–1259
Lummis SC, Beene DL, Lee LW, Lester HA, Broadhurst RW, Dougherty DA (2005) Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel. Nature 438(7065):248–252
Marchand S, Devillers-Thiery A, Pons S, Changeux JP, Cartaud J (2002) Rapsyn escorts the nicotinic acetylcholine receptor along the exocytic pathway via association with lipid rafts. J Neurosci 22:8891–8901
Marsh D, Barrantes FJ (1978) Immobilized lipid in acetylcholine receptor-rich membranes from Torpedo marmorata. Proc Natl Acad Sci USA 75(9):4329–4333
McCarthy MP, Moore MA (1992) Effects of lipids and detergents on the conformation of the nicotinic acetylcholine receptor from Torpedo californica. J Biol Chem 267(11):7655–7663
Methot N, Demers CN, Baenziger JE (1995) Structure of both the ligand- and lipid-dependent channel-inactive states of the nicotinic acetylcholine receptor probed by FTIR spectroscopy and hydrogen exchange. Biochemistry 34(46):15142–15149
Mitra A, Bailey TD, Auerbach AL (2004) Structural dynamics of the M4 transmembrane segment during acetylcholine receptor gating. Structure 12(10):1909–1918
Nashmi R, Xiao C, Deshpande P, McKinney S, Grady SR, Whiteaker P, Huang Q, McClure-Begley T, Lindstrom JM, Labarca C, Collins AC, Marks MJ, Lester HA (2007) Chronic nicotine cell specifically upregulates functional alpha 4* nicotinic receptors: basis for both tolerance in midbrain and enhanced long-term potentiation in perforant path. J Neurosci 27(31):8202–8218
Nury H, Bocquet N, Le Poupon C, Raynal B, Haouz A, Corringer PJ, Delarue M (2010) Crystal structure of the extracellular domain of a bacterial ligand-gated ion channel. J Mol Biol 395(5):1114–1127
Paradiso K, Zhang J, Steinbach JH (2001) The C terminus of the human nicotinic alpha4beta2 receptor forms a binding site required for potentiation by an estrogenic steroid. J Neurosci 21(17):6561–6568
Pons S, Sallette J, Bourgeois JP, Taly A, Changeux JP, Devillers-Thiery A (2004) Critical role of the C-terminal segment in the maturation and export to the cell surface of the homopentameric alpha 7-5HT3A receptor. Eur J Neurosci 20(8):2022–2030
Shen XM, Deymeer F, Sine SM, Engel AG (2006) Slow-channel mutation in acetylcholine receptor alphaM4 domain and its efficient knockdown. Ann Neurol 60(1):128–136
Sturgeon RM, Baenziger JE (2010) Cations mediate interactions between the nicotinic acetylcholine receptor and anionic lipids. Biophys J 98(6):989–998
Tamamizu S, Guzman GR, Santiago J, Rojas LV, McNamee MG, Lasalde-Dominicci JA (2000) Functional effects of periodic tryptophan substitutions in the alpha M4 transmembrane domain of the Torpedo californica nicotinic acetylcholine receptor. Biochemistry 39(16):4666–4673
Tobimatsu T, Fujita Y, Fukuda K, Tanaka K, Mori Y, Konno T, Mishina M, Numa S (1987) Effects of substitution of putative transmembrane segments on nicotinic acetylcholine receptor function. FEBS Lett 222(1):56–62
Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol 346(4):967–989
Vallejo YF, Buisson B, Bertrand D, Green WN (2005) Chronic nicotine exposure upregulates nicotinic receptors by a novel mechanism. J Neurosci 25(23):5563–5572
Xiu X, Hanek AP, Wang J, Lester HA, Dougherty DA (2005) A unified view of the role of electrostatic interactions in modulating the gating of Cys loop receptors. J Biol Chem 280(50):41655–41666
Xu Y, Barrantes FJ, Luo X, Chen K, Shen J, Jiang H (2005) Conformational dynamics of the nicotinic acetylcholine receptor channel: a 35-ns molecular dynamics simulation study. J Am Chem Soc 127(4):1291–1299
Conflict of interest statement
We declare no conflict of interest
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Baenziger, J.E., daCosta, C.J.B. Molecular mechanisms of acetylcholine receptor–lipid interactions: from model membranes to human biology. Biophys Rev 5, 1–9 (2013). https://doi.org/10.1007/s12551-012-0078-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12551-012-0078-7