Abstract
GluK3-kainate receptors are atypical members of the iGluR family that reside at both the pre- and postsynapse and play a vital role in the regulation of synaptic transmission. For a better understanding of structural changes that underlie receptor functions, GluK3 receptors were trapped in desensitized and resting/closed states and structures analyzed using single particle cryo-electron microscopy. While the desensitized GluK3 has domain organization as seen earlier for another kainate receptor-GluK2, antagonist bound GluK3 trapped a resting state with only two LBD domains in dimeric arrangement necessary for receptor activation. Using structures as a guide, we show that the N-linked glycans at the interface of GluK3 ATD and LBD likely mediate inter-domain interactions and attune receptor-gating properties. The mutational analysis also identified putative N-glycan interacting residues. Our results provide a molecular framework for understanding gating properties unique to GluK3 and exploring the role of N-linked glycosylation in their modulation.
Highlights
Ionotropic glutamate receptors mediate the majority of fast excitatory neurotransmission at the chemical synapses in the central nervous system (CNS)
Current advances in the field of ionotropic glutamate receptor biology indicates that KA receptors are involved in multifunctional neuronal activity and have a profound role in health and diseases[2,43,44,45]
Binding of agonist to the resting state receptor leads to a short-lived active state, which immediately relaxes to a desensitized state to relieve the strain caused by the activated state onto linkers between ligand binding (LBD) and TM29,34
Summary
Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory neurotransmission at the chemical synapses in the central nervous system (CNS). In contrast to the AMPA and NMDA receptors that are primarily localized on the post-synaptic membrane and are directly involved in neurotransmission, increasing evidence has shown that KA receptors are expressed at both the presynaptic and postsynaptic sites. KA receptors are abundantly expressed in hippocampus and cerebellum; display characteristic slow kinetics, are mainly involved in long-term memory formation and motor control[5,6] They are divided into two families consisting of the “low-affinity” glutamate binding subunits (GluK1-GluK3) that form functional homomeric ion channels and “high-affinity” subunits (GluK4 and GluK5) that form functional receptors only on assembly with “low-affinity” subunits[7,8,9]. IGluRs including GluK3, are extensively N-glycosylated which likely imparts an additional level of regulation of their functions These glycans have been reported to affect the trafficking, gating properties[16,17,18] and assembly of iGluRs19–24. Amplitudes of normalized currents for wild-type and GluK3EM evoked on the application of 30 mM glutamate is shown in inset c
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