Fellow's research: Cryo-EM reveals how not all glutamate receptors are built the same

11 Jan 2020

Fellow's research: Cryo-EM reveals how not all glutamate receptors are built the same

Janesh Kumar, Intermediate Fellow, National Centre for Cell Science, Pune

In the latest research, our team at National Centre for Cell Science (NCCS) has captured the first 3D views of the GluD1-subtype glutamate receptor. These special receptors play crucial roles in motor coordination and learning, high-frequency hearing, and many other brain functions. They are also linked to social and cognitive deficits, and to neurological disorders like schizophrenia and cocaine addiction.

Information relay in the brain occurs through chemical messengers called neurotransmitters that act by binding with their ‘receptors’ on neurons. Majority (~60%) of excitatory brain signalling is carried out by glutamate receptor ion channels, present on the synaptic junctions of neurons. These receptors are integral to functions such as learning and memory. However, unlike other members of the family like AMPA, kainate and NMDA receptors, the orphan delta receptors are not activated by neurotransmitter glutamate binding. This has been puzzling the researchers in the field for decades. We decided to look for clues in the structural differences that might be responsible for this inactivity and unique functions of orphan delta receptors.

To visualise the receptors, GluD1 was complexed with ligands that stabilize receptor and enable imaging and structure determination via electron microscopy. This was critical for imaging these receptors as the inherent conformational variations limit the details that could be observed. Cryo-EM is a revolutionary technique that images several thousand of molecules in frozen state and combines the 2D images generated to build a three-dimensional view. The developers of this method Joachim Frank, Jacques Dubochet and Richard Henderson were awarded Chemistry Nobel Prize in 2017 to recognise their contribution.

Figure 1 Model depicting the interaction mediated by GluD receptors at the synapse. Receptor structure is shown in form of ribbons fitted in EM density map highlighting unique non-swapped architecture observed in glutamate receptor ion channel family.

The findings reveal an unprecedented domain organization of GluD1 receptors different from other members of the glutamate receptor family. We provide evidence that glutamate receptor ion channels are not built the same, and also propose a new model for the interactions of this receptor with other proteins at the synapse. Our discovery of the GluD1 structure corrects the decade old model of the receptor that was built on other members of the glutamate receptor family.

This research, published in the journal Nature Structural and Molecular Biology, is the first to reveal the structure of a full-length orphan GluD1 receptor. Our findings create a solid ground for further understanding the functions of these receptors and developing therapeutics for neurological disorders linked with GluD1 dysfunction. This discovery could lead to novel insights into the mechanism behind a wide range of nervous system disorders and diseases.

Cryo-EM structures of the ionotropic glutamate receptor GluD1 reveal a non-swapped architecture. Ananth Prasad Burada, Rajesh Vinnakota & Janesh Kumar. Nature Structural & Molecular Biology. Volume 27, pages84–91(2020). DOI: 10.1038/s41594-019-0359-y