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The Journal of Neuroscience, June 15, 2001, 21(12):4162-4172

Channel-Lining Residues of the AMPA Receptor M2 Segment: Structural Environment of the Q/R Site and Identification of the Selectivity Filter

Thomas Kuner^{1, 2}, Christine Beck¹, Bert Sakmann², and Peter H. Seeburg¹

¹ Abteilung Molekulare Neurobiologie, ² Abteilung Zellphysiologie, Max-Planck Institut für Medizinische Forschung, 69120 Heidelberg, Germany

In AMPA receptor channels, a single amino acid residue (Q/R site) of the M2 segment controls permeation of calcium ions, single-channel conductance, blockade by intracellular polyamines, and permeation of anions. The structural environment of the Q/R site and its positioning with regard to a narrow constriction were probed with the accessibility of substituted cysteines to positively and negatively charged methanethiosulfonate reagents, applied from the extracellular and cytoplasmic sides of the channel. The accessibility patterns confirm that the M2 segment forms a pore loop with the Q/R site positioned at the tip of the loop (position 0) facing the extracellular vestibule. Cytoplasmically accessible residues on the N- and C-terminal sides of position 0 form the ascending -helical (8 to 1) and descending random coil (+1 to +6) components of the loop, respectively. Substitution of a glycine residue at position +2 with alanine strongly decreased the permeability of organic cations, indicating that position +2 contributes to the narrow constriction. The anionic 2-sulfonatoethyl-methanethiosufonate reacted with a cysteine at position 0 only from the external side and with cysteines at positions +1 to +4 only from the cytoplasmic side. These results suggest that charge selectivity occurs external to the constriction (+2) and possibly involves interactions of ions with the negative electrostatic potential created by the dipole of the -helix formed by the ascending limb of the loop.

Key words: glutamate receptor; AMPA; narrow constriction; pore loop; SCAM; organic cations; polyamines

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21124162-11$05.00/0

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