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Different gating mechanisms in glutamate receptor and K+ channels.
Sobolevsky AI
,
Yelshansky MV
,
Wollmuth LP
.
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The basic structural features of channel gating in glutamate receptors (GluRs) remain unknown. Here we used covalent modification of substituted cysteines and fast agonist application to study the contribution of the M3 segment in AMPA receptor GluR-A subunits to channel structure and gating. The pattern of accessibility of substituted cysteines to extracellularly applied methanethiosulfonate reagents and the rates of their modification by these reagents, measured in either the presence or absence of glutamate, indicate that M3 forms an alpha-helix that lines the pore of the channel and is involved in gating-related movements. The voltage dependence of modification rates places the tip of the M2 loop (the Q/R site) close to the middle of M3. All of these results are consistent with pore-forming domains in GluR and K+ channels having a similar structure but inverted membrane topology. Nevertheless, GluRs lack a glycine residue at a homologous structural position as the gating hinge glycine in K+ channels. Moreover, simultaneous substitution of the only two glycines in M3 of GluR-A with alanines produced channels with gating properties indistinguishable from wild type. Given the unique role of glycines in the flexibility ofalpha-helices, our results indicate that the M3 segment in GluR does not contain a glycine gating hinge and suggest that, in contrast to the homologous domain in K+ channels, M3 is rigid during gating. The different positioning and functional significance of glycines in a key structural domain may represent the basis for the distinct features of gating in GluR and K+ channels.
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