Molecular basis of the charge selectivity of nicotinic acetylcholine receptor and related ligand-gated ion channels.
Nicotinic acetylcholine receptors are homo- or heteropentameric proteins belonging to the superfamily of receptor channels including the glycine and GABA-A receptors. Affinity labelling and mutagenesis experiments indicated that the M2 transmembrane segment of each subunit lines the ion channel and is coiled into an alpha-helix. Comparison of the M2 sequence of the cation-selective alpha 7 nicotinic receptor to that of the anion-selective alpha 1 glycine receptor identified amino acids involved in charge selectivity. Mutations of the alpha 7 homo-oligomeric receptor within (or near) M2, namely E237A, V251T and a proline insertion P236' were shown to convert the ionic selectivity of alpha 7 from cationic to anionic. Systematic analysis of each of these three mutations supports the notion that the conversion of ionic selectivity results from a local structural reorganization of the 234-238 loop. The 234-238 coiled loop, previously shown to lie near the narrowest portion of the channel, is thus proposed to contribute directly to the charge selectivity filter. A possible functional analogy with the voltage-gated ion channels and related receptors is discussed.
Corringer
P J
PJ
Unité de recherche associée au Centre National de la Recherche Scientifique D1284, Institut Pasteur, Paris, France.
Bertrand
S
S
Galzi
J L
JL
Devillers-Thiéry
A
A
Changeux
J P
JP
Bertrand
D
D
D000595:Amino Acid Sequence; D000838:Anions; D002412:Cations; D004563:Electrochemistry; D015640:Ion Channel Gating; D008024:Ligands; D008969:Molecular Sequence Data; D009154:Mutation; D011978:Receptors, Nicotinic / Q000737:chemistry*
D000838:Anions; D002412:Cations; D008024:Ligands; D011978:Receptors, Nicotinic