The research on delta glutamate (GluD) receptors was conducted by a team of University of Texas Health Science Center at Houston researchers, including first author Elisa Carrillo, PhD, and senior author Vasanthi Jayaraman, PhD, and was published in Science Advances in December 2021.

The editor-in-chief of the review journal Trends in Neurosciences, asked Popescu to write a review of the findings. She and a postdoctoral associate in her lab, Jamie A. Abbott, PhD, collaborated on “Homecoming of the Estranged GluD Channels,” which was published April 27.

“He was familiar with my work and expertise in the area of ion channels, and especially in ionotropic glutamate receptors and reached out to me to see whether I could write a commentary on the paper to explain the context of the findings, their implications and to highlight some of the questions to be addressed in future work,” Popescu says.

“The work by Carrillo et al. is noteworthy because it demonstrates for the first time, in a definitive manner, that GluD receptors function as ligand-gated ion channels in the brain,” she says.

Popescu says targeting GluD receptors in potential novel therapeutic treatments may be fruitful, specifically for ataxias and other movement disorders.

“Importantly, we know these receptors are expressed in many brain regions other than the cerebellum,” she says. “It is unclear what they do there. The findings by Carrillo et al. provides us with tools to begin asking these questions.”

Among the neurological diseases that GluD receptors are implicated in are cerebellar neurodegeneration, spinocerebellar ataxia, schizophrenia and autism spectrum disorders.

“This work is important because it opens the way for functional investigations into the role of GluD receptors in synaptic transmission, and more generally in brain development and function,” Popescu says.

“This exciting breakthrough in neuroscience research has many implications for the potential treatment of neurological diseases, a subject close to my heart,” says Allison Brashear, MD, MBA, UB’s vice president for health sciences and dean of the Jacobs School of Medicine and Biomedical Sciences. “The Jacobs School is proud to have such experts as Dr. Popescu among its faculty members. Her lab’s commentary on this study skillfully elucidates the context of its findings.”

GluD receptors were first discovered due to their similarity with the three main ionotropic glutamate receptors in the central nervous system: AMPA receptors (GluA proteins), NMDA receptors (GluN proteins) and kainate receptors encoded by GluK proteins.

These three classes of receptors are the principal synaptic receptors in the brain and spinal cord and function as glutamate-activated excitatory ion channels, Popescu explains.

“GluD receptors are clearly important for normal brain function because animals lacking these receptors die immediately after birth,” she says. “However, how they work and what exactly they do has remained a mystery until now.”

GluD receptors have very similar structures to the other three classes of ionotropic glutamate receptors, but they are insensitive to glutamate.

Previous research has established that they don’t even bind glutamate; instead, they bind the neurotransmitter glycine. However, exposing them to glycine, even at high concentrations, failed to produce current, Popescu points out.

“For this reason, for more than 30 years GluD receptors have been classified as ‘orphan’ receptors, with the belief that they may be activated by a yet unidentified endogenous factor,” she says.

Popescu says the GluD receptor has been famous in the neuroscience literature because it turned out to be the molecular defect responsible for the ataxic behavior of the Lurcher mouse.

This type of mouse arose spontaneously in a normal mouse colony in the 1950s and was easily identifiable by its lurching movements and it has been established this behavior is caused by a unique mutation in the GluD receptor.

“It turned out that the defective receptor was leaking current, or in other words, functions as an ‘always open’ ion channel,” Popescu says. “This excessive excitation causes neuronal loss in the cerebellum and in movement disorders such as ataxia. These observations show that GluD receptors can function as ion channels when mutated, but it is still unresolved if the normal, healthy channels do so.”

Popescu says the work of Carrillo et al. “integrates all this into a unified, consistent and elegant new hypothesis.”

“It demonstrates for the first time that like all other ionotropic glutamate receptors, GluD receptors function as ligand-gated ion channels; when integrated in a transcellular structure, they respond to the neurotransmitter glycine with an excitatory current,” she says.

In the new work, rather than recording from isolated GluD receptors, the authors recorded from GluD receptors that formed transcellular bridges together with the neuronal proteins cerebellin and neurexin, Popescu notes.

“Glycine treatment elicited excitatory current from linked cells, but not from cells that were mechanically separated from each other or from cells that lacked either GluD receptors, cerebellin or neurexin,” she says. “Moreover, they showed that the glycine-gated ionotropic function of GluD receptors can be revealed simply by bracing their extracellular domains by chemical cross-linking.”

“The race is on to find bracing partners in other regions, endogenous regulators and the effects of the current on brain function.”