New structures reveal a novel architecture of an important brain receptor involved in several key brain functions and implicated in multiple neuronal disorders including schizophrenia, cognitive deficits, and cerebral ataxia.
National Centre for Cell Science (NCCS) researchers have captured the first three dimensional views of the GluD1-subtype glutamate receptor. These special receptors play crucial roles in motor coordination and motor learning, high-frequency hearing and are also key to many other brain functions. They are linked to social and cognitive deficits and to neuronal disorders like schizophrenia and cocaine addiction.
The findings were published in Nature Structural and Molecular Biology.
“Our results reveal an unprecedented domain organization of GluD1 receptors distinct from that observed in other members of the glutamate receptor family,” said Janesh Kumar, Ph.D., Scientist at Laboratory of membrane protein biology, NCCS, Pune and senior author of the paper. “This highlights the fact that not all glutamate receptor ion channels are built the same and gives insights into molecular underpinnings of receptor functions”
Majority (~60%) of excitatory brain signalling is carried out by glutamate receptor ion channels that are present on the synaptic junctions of neurons. These receptors form cornerstones of a multitude of high cognitive functions, including 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. The current discovery offers clues into 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” says Ananth P Burada, a Ph.D. candidate at NCCS and first author of the paper.
“These new results have implications for our understanding of functions of this class of glutamate receptors,” says Rajesh Vinnakota, Ph.D., a postdoctoral fellow at NCCS and co-author on the paper. “Understanding these processes will impact future studies on glutamate receptor signalling in neurodegenerative diseases as well as drug design.”
GluD1 structure corrects the decade-old model of the receptor that was built on other members of the glutamate receptor family. Authors also propose a new model for the interaction the receptor makes with other proteins at the synapse. Thus this study creates a robust platform for understanding the functions of these receptors and developing therapeutics to treat neurological disorders that are associated with GluD1 dysfunction.
To study the receptor, Kumar’s team used cryo-electron microscopy, 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.