New Images of Brain Receptor Could Lead to MS Therapy Breakthroughs

Scientists at Columbia University Medical Center have captured new images that for the first time offer a 3-dimensional picture of how the AMPA-subtype glutamate receptor opens and closes.

The new information could have significant impacts on efforts to develop therapies for multiple sclerosis (MS), among other diseases.

Senior author Alexander Sobolevsky, PhD, said the new study solves a mystery scientists have been working on since the 1990s: How does the neurotransmitter glutamate open glutamate receptor ion channels?

The question is critical because glutamate receptors are key to a number of cognitive functions, including memory and learning. More specifically, AMPA-subtype glutamate receptors are related to rapid perception and reaction. Sobolevsky and colleagues were able to answer the question by fusing AMPA glutamate receptors with stargazin, a regulatory receptor that causes the channel to open.

It turns out that AMPA glutamate receptors open in a fashion similar to a camera’s iris, with the four units of the tetrameric structure twisting outward to widen the receptor’s channel, and specialized channel lining helping to guide the ions through.

Sobolevsky, an associate professor of biochemistry and molecular biophysics at Columbia, said glutamate receptors appear to differ from other representatives of the tetrameric ion channel family in that they have a unique gating hinge in the pore-forming helices M3.

“The strain created by the neurotransmitter glutamate binding to the ligand-binding domains of the glutamate receptor, which is applied to linkers leading to the ion channel, kinks the M3 helices at the gating hinge and allows a unique widening of the ion channel pore,” Sobolevsky said. “This gating hinge is represented by a 100% conserved alanine in the middle of a signature protein sequence region of ionotropic glutamate receptors and we expect that all representatives of this family, including AMPA, kainate, and NMDA receptors will have the same universal mechanism of ion channel gating.”

Sobolevsky said the findings represent a “fundamental insight” into how glutamate interacts with these proteins to mediate neurotransmission.

The research could have implications for a wide array of diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and glaucoma. When it comes to MS, Sobolevsky said the new insights into AMPA glutamate receptors could prove particularly important.

“Glutamate neurotoxicity is a major factor that accompanies demyelination and axonal degeneration during the course of MS,” Sobolevsky said. “Sustained activation of AMPA, NMDA, and kainate subtypes of ionotropic glutamate receptors damages oligodendrocytes.”

MS patients have been shown to have increased levels of glutamate receptors, in neuronal cells and T cells, the latter of which have also been found to produce and release their own glutamate.

In animal models, therapies that inhibit glutamate receptors have successfully countered neurological symptoms and reduced the expression of pro-inflammatory cytokines in the brain, Sobolevsky noted.

“Correspondingly, glutamate receptors emerge as a promising target for synthesis of new drugs for MS treatment,” Sobolevsky said.

Unfortunately, currently available drugs targeting glutamate receptors have a number of serious neurobehavioral side effects. Thus, finding new and better drug candidates is a matter of “enormous importance,” Sobolevsky said.

He hopes his study helps pave the way for that to happen.

“Through showing the open conformation of glutamate receptors (the state most relevant to disease) and understanding the mechanism by which glutamate receptors gate, our study greatly increases the chances of identifying new drugs as a result of structure-guided design strategies based on our data,” Sobolevsky said.

The study, “Channel opening and gating mechanism in AMPA-subtype glutamate receptors,” is was published online in the journal Nature.

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