Atomistic simulations explain mutational effects on ion modulation and kainate receptor activity

 Ionotropic glutamate receptors, iGluRs
 Kainate‐selective iGluRs require binding of external ions for activation
 What are the roles of these ions, especially in the process of desensitisation?
Two cross‐linked mutants with highly different phenotypes:
Continuously active, no desensitisation
Only short , low‐conducting openings with long closures
D776K
K776 substitutes for cation binding, occupies the cation site and keeps LBD interface together
Y521C/L783C
Ions are relea‐
sed and inter‐
face opens up, consistent with theories on desensitisation.
WT
Y521C/L783C
Occupancy of the cation pocket controls switching between activated and desensitised states of KARs. If the ligand unbinds before the cation, the receptor is deactivated, whereas if the cations unbind first, desensitisation proceeds.

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