Fellow's research: A three-dimensional view of a key brain receptor protein
24 Jun 2020
Janesh Kumar, Intermediate Fellow, NCCS, Pune
Our latest research published in the Journal of Structural Biology, is the first to provide insights into the structure of a key receptor protein, Glutamate Delta-2 (GluD2), present in the membrane of the neurons that play a key role in synaptogenesis and synaptic plasticity and is associated with multiple neuronal disorders like schizophrenia, autism spectrum disorder, cerebellar ataxia, intellectual disability, paraplegia, retinal dystrophy, etc.
GluD2 receptor protein, predominantly expressed in Purkinje cells in the cerebellum, belongs to a family of glutamate receptor ion channels that mediate majority of excitatory neuronal signalling in the central nervous system. Unlike other members of the glutamate receptor ion channel family, endogenous ligands for GluD1 and GluD2 receptors are not known and hence they are grouped into a subfamily named as orphan delta receptors.
Using cryo-electron microscopy, we elucidated the three-dimensional views of the GluD2-subtype glutamate receptor. The structures confirm that both the members of orphan delta family have unique domain organization which is distinct from that observed in other members of the glutamate receptors family like AMPA, kainate or NMDA receptors.
Figure 1: Structures of GluD1 and GluD2 shown side by side highlighting the unique non-swapped architecture observed in orphan delta glutamate receptor ion channel family. Each subunit of the tetrameric receptor is colored uniquely to emphasize the domain organization.
The current study also reveals the difference that exists within orphan delta receptor family that could be important for the unique functional properties of GluD1 and GluD2 receptors. Taken together, these findings highlight the fact that glutamate receptor ion channels are not built the same and provide key insights into molecular underpinnings of delta receptor functions.
GluD2 structures along with the GluD1 receptor structures reported by the team earlier this year in Nature Structural and Molecular Biology redefine and correct the decade old model of the receptor that was built on other members of the glutamate receptor family. Thus, our work on GluD receptor family provides molecular blueprints for understanding the functions of these receptors. These new findings may also enable exploration of novel therapeutics targeting neuronal disease associated with GluD receptor dysfunction.
The Architecture of GluD2 Ionotropic Delta Glutamate Receptor Elucidated by cryo-EM. Ananth Prasad Burada, Rajesh Vinnakota, and Janesh Kumar. Journal of Structural Biology (2020): 107546.
Neuronal synapse, artwork. Credit: Stephen Magrath. CC0 1.0 Universal