Kainate receptors are members of the ionotropic glutamate receptor family which consists of three primary subunits (GluK1–3) capable of forming homo- or hetero-tetramers, and two secondary subunits (GluK4–5) that can only form hetero-tetramers along with the primary subunits. They are localized pre-, post-, and extrasynaptically, where they both modulate neurotransmitter release and mediate excitatory neurotransmission. The synaptic cleft environment is subject to activity dependent pH fluctuations due to the release of acidic synaptic vesicles having pH 5.3–5.7. Also, sustained acidification of synapse occurs in pathological conditions like ischemia and stroke. Here, we combine electrophysiology and single-molecule FRET (smFRET) to investigate how acidic pH affects the structure and function of homomeric GluK2 receptors, and elucidate the underlying mechanism. The electrophysiology experiments reveal that, unlike AMPA and NMDA receptors, the amino terminal domail (ATD) does not contribute to pH sensing; instead, one of the two histidine residues in the agonist binding domain (ABD), His792, is crucial in GluK2 receptors. smFRET measurements further show that at acidic pH the ABD adapts to a “decoupled” conformation indicating the desensitized like state which was not observed in the smFRET measurements on H792L mutant. These findings highlight the unique mechanism of pH dependent modulation in kainate receptors and show how the synaptic environment may influence the excitatory neurotransmission.
Apotikar et al. (Sun,) studied this question.
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