Abstract
Kainate receptors (KARs) are L-glutamate-gated ion channels that regulate synaptic transmission and modulate neuronal circuits. KARs have strict assembly rules and primarily function as heteromeric receptors in the brain. A longstanding question is how KAR heteromer subunits organize and coordinate together to fulfill their signature physiological roles. Here we report structures of the GluK2/GluK5 heteromer in apo, antagonist-bound, and desensitized states. The receptor assembles with two copies of each subunit, ligand binding domains arranged as two heterodimers and GluK5 subunits proximal to the channel. Strikingly, during desensitization, GluK2, but not GluK5, subunits undergo major structural rearrangements to facilitate channel closure. We show how the large conformational differences between antagonist-bound and desensitized states are mediated by the linkers connecting the pore helices to the ligand binding domains. This work presents the first KAR heteromer structure, reveals how its subunits are organized, and resolves how the heteromer can accommodate functionally distinct closed channel structures.
Highlights
Ionotropic glutamate receptors respond to the neurotransmitter L-glutamate (L-Glu) to mediate the majority of fast excitatory synaptic transmission in the human brain (Dingledine et al, 1999)
In our study we show that the heteromer assembles with two copies of each subunit, with GluK2 and GluK5 ligand binding domain (LBD) arranged in alternating fashion around the receptor central axis and with GluK5 subunits proximal to the pore and GluK2 subunits
Morph for GluK2/K5em ligand binding domain (LBD)-transmembrane domain (TMD) assembly viewed from the top
Summary
Ionotropic glutamate receptors (iGluRs) respond to the neurotransmitter L-glutamate (L-Glu) to mediate the majority of fast excitatory synaptic transmission in the human brain (Dingledine et al, 1999). Receptors containing either GluK4 or GluK5 are linked to diseases such as depression (Catches et al, 2012), epilepsy (Das et al, 2012), autism (Aller et al, 2015), and schizophrenia (Greenwood et al, 2016) Despite their significance, no KAR heteromer structure has been reported, which presents a major knowledge gap made more salient by recently reported structures of NMDAR (Karakas and Furukawa, 2014; Lee et al, 2014; Luet al., 2017) and AMPAR heteromers (Herguedas et al, 2019; Zhao et al, 2019). We report structures of the GluK2/GluK5 heteromer (GluK2/K5), proposed to be the major KAR in the brain (Herb et al, 1992; Petralia et al, 1994), in resting (apo), antagonist-bound (6cyano-7-nitroquinoxaline-2,3-dione [CNQX]), and agonist-bound (L-Glu) desensitized states. This work provides an expanded foundation for understanding differences and similarities among KAR (Kumari et al, 2019; Meyerson et al, 2014a; Meyerson et al, 2016), AMPAR (Herguedas et al, 2019; Zhao et al, 2019), NMDAR (Karakas and Furukawa, 2014; Lee et al, 2014; Luet al., 2017), and recently characterized ionotropic orphan delta (GluD) receptor structures (Burada et al, 2020a; Burada et al, 2020b)
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