scholarly journals Nonselective cation permeation in an AMPA-type glutamate receptor

2021 ◽  
Vol 118 (8) ◽  
pp. e2012843118
Author(s):  
Johann Biedermann ◽  
Sebastian Braunbeck ◽  
Andrew J. R. Plested ◽  
Han Sun
Keyword(s):  
Glutamate Receptor ◽  
Ampa Receptors ◽  
Binding Sites ◽  
Alkali Metals ◽  
Molecular Mechanisms ◽  
Md Simulations ◽  
Cation Channel ◽  
Ion Binding ◽  
Anion Permeation ◽  
Ion Binding Sites

Fast excitatory synaptic transmission in the central nervous system relies on the AMPA-type glutamate receptor (AMPAR). This receptor incorporates a nonselective cation channel, which is opened by the binding of glutamate. Although the open pore structure has recently became available from cryo-electron microscopy (Cryo-EM), the molecular mechanisms governing cation permeability in AMPA receptors are not understood. Here, we combined microsecond molecular dynamic (MD) simulations on a putative open-state structure of GluA2 with electrophysiology on cloned channels to elucidate ion permeation mechanisms. Na+, K+, and Cs+ permeated at physiological rates, consistent with a structure that represents a true open state. A single major ion binding site for Na+ and K+ in the pore represents the simplest selectivity filter (SF) structure for any tetrameric cation channel of known structure. The minimal SF comprised only Q586 and Q587, and other residues on the cytoplasmic side formed a water-filled cavity with a cone shape that lacked major interactions with ions. We observed that Cl− readily enters the upper pore, explaining anion permeation in the RNA-edited (Q586R) form of GluA2. A permissive architecture of the SF accommodated different alkali metals in distinct solvation states to allow rapid, nonselective cation permeation and copermeation by water. Simulations suggested Cs+ uses two equally populated ion binding sites in the filter, and we confirmed with electrophysiology of GluA2 that Cs+ is slightly more permeant than Na+, consistent with serial binding sites preferentially driving selectivity.

scholarly journals Non-selective cation permeation in an AMPA-type glutamate receptor

2020 ◽  
Author(s):  
Johann Biedermann ◽  
Sebastian Braunbeck ◽  
Andrew J. R. Plested ◽  
Han Sun
Keyword(s):  
Molecular Dynamics ◽  
Ion Channel ◽  
Binding Site ◽  
Glutamate Receptor ◽  
Binding Sites ◽  
Alkali Metals ◽  
Molecular Mechanisms ◽  
Cation Channel ◽  
Ion Binding ◽  
Major Ion

AbstractFast excitatory synaptic transmission in the central nervous system relies on the AMPA-type glutamate receptor (AMPAR). This receptor incorporates a non-selective cation channel which is opened by the binding of glutamate. Although the open pore structure has recently became available from cryo-electron microscopy (Cryo-EM), the molecular mechanisms governing cation permeability in AMPA receptors are not understood. Here, we combined microsecond molecular dynamics (MD) simulations on a putative open state structure of GluA2 with electrophysiology on cloned channels to elucidate ion permeation mechanisms. Na+, K+ and Cs+ permeated at physiological rates, consistent with a structure that represents a true open state. A single major ion binding site for Na+ and K+ in the pore represents the simplest selectivity filter (SF) structure for any tetrameric cation channel of known structure. The minimal SF comprised only Q586 and Q587, and other residues on the cytoplasmic side formed a cone- shaped void that lacked major interactions with ions. We observed Cl- invasion of the upper pore, explaining anion permeation in the edited form of GluA2. A permissive architecture of the SF accommodated different alkali metals in distinct solvation states to allow rapid, non-selective cation permeation, and co-permeation by water. Simulations suggested Cs+ uses two equally populated ion binding sites in the filter and we confirmed with electrophysiology of GluA2 that Cs+ is more permeant than Na+, consistent with serial binding sites preferentially driving selectivity.Significance StatementAMPA-type glutamate receptors (AMPARs) are key actors in neurotransmission, making the final step in a relay of excitability from one brain cell to another. The receptor contains an integral ion channel, which, when opened by neurotransmitter binding, permits sodium and other cations to cross the cell membrane. We investigated permeation of sodium, potassium and caesium in an AMPAR at the atomistic level using a computational molecular dynamics approach on a structure with the ion channel pore in a presumably open state. We determined that the region selecting between cations is the simplest of any channel of this type. Distinct from ion channels that select single ion species, cations are never fully dehydrated and have only one major ion binding site in the filter. Simulations suggested two similar binding sites for caesium, and studies of AMPARs in mammalian cell membranes showed that this makes caesium more permeant than sodium.

scholarly journals Selectivity of externally facing ion-binding sites in the Na/K pump to alkali metals and organic cations

2010 ◽  
Vol 107 (43) ◽  
pp. 18718-18723 ◽  
Author(s):  
I. M. Ratheal ◽  
G. K. Virgin ◽  
H. Yu ◽  
B. Roux ◽  
C. Gatto ◽  
...  
Keyword(s):  
Binding Sites ◽  
Alkali Metals ◽  
Organic Cations ◽  
Ion Binding ◽  
Ion Binding Sites

scholarly journals Synthesis and Photoregulated Metal Coordination of Azobenzene Polymer Having Ion Binding Sites

1991 ◽  
Vol 23 (2) ◽  
pp. 127-134 ◽  
Author(s):  
Masato Nanasawa ◽  
Takahiro Nishiyama ◽  
Hiroyoshi Kamogawa
Keyword(s):  
Binding Sites ◽  
Metal Coordination ◽  
Ion Binding ◽  
Azobenzene Polymer ◽  
Ion Binding Sites

The Effect Of Metal Ions On Human Factor IX Antigenicity

1981 ◽  
Author(s):  
R M Lewis ◽  
H M Reisner ◽  
B C Abels ◽  
H R Roberts
Keyword(s):  
Divalent Cation ◽  
Binding Sites ◽  
Human Factor ◽  
Antibody Binding ◽  
Factor Ix ◽  
Ion Binding ◽  
Human Factor Ix ◽  
Excess Mg ◽  
Ion Binding Sites ◽  
Two Populations

Affinity chromatography of an inhibitor to human factor IX (F.IX) separated the antibody into two populations. The ion dependent population of antibodies had an absolute divalent cation (Me++) binding requirement. The non-ion dependent population bound F.IX equally in the presence or absence of Me++. The concentration of Me++ required for ½ the maximum ion dependent antibody binding (½ max) was (in nM) Ca++ 0.40, Mn++ 0.05, Sr++ 0.70 and Mg++ 0.65.Ca++ potentiated the binding of antibody in the presence of excess Mg++. In addition, the ½ max for Ca++ was reduced about four fold. These observations are consistent with separate binding sites on the F.IX molecule for Ca++ and Mg++ and potentiation of Ca++ binding by Mg++. Scat- chard analysis of ion dependent antibody binding indicates about a 10 fold greater affinity of antibody in the presence of Ca++ than Mg++. In the presence of both cations, affinity was at least as high as in the presence of Ca++ alone supporting the presence of separate ion binding sites on the F.IX molecule.

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