New Signaling Pathway Insights Could Lead to Novel Neurological Disorder Therapies

Northwestern Medicine scientists have demonstrated an alternate method of signaling by a class of proteins called group I metabotropic glutamate receptors, which are thought to be promising targets in the treatment of a variety of neurological and psychiatric disorders.

The findings, recently published in Nature Communications, could inform ongoing drug development for a number of pathologies, including schizophrenia, pain, Parkinson’s disease and especially fragile X syndrome, a genetic condition that causes developmental disabilities.

The group I metabotropic glutamate receptors, called mGluR1 and mGluR5, serve as modulators of nerve cell excitability and synaptic transmission, or the communication between neurons. Traditionally, they have been described as signaling through a process called G-protein coupling.

In the current study, however, the scientists demonstrated that not all signaling by group I mGluRs is mediated by G proteins. In fact, in some cases they utilize pathways requiring a different protein called β-arrestin2.

“Given that group I mGluRs seem like promising drug targets, at least in these early days, you want to know more about how they really work. And that’s where our study comes in,” said Geoffrey Swanson, PhD, professor of Pharmacology, the lead author of the paper. “We showed that the classical model is too simple, and demonstrated an unexpected way of signaling, downstream of receptor activation.”

By comparing normal mice with mice that lacked either β-arrestin1 or β-arrestin2, and examining various physiological parameters, they discovered that β-arrestin2 was necessary for some forms of mGluR signaling that change the strength of excitatory synapses in the hippocampus.

Future novel drugs might manipulate either pathway, giving scientists more flexibility in how they might tackle neurological disorders.

“That’s the promise of this study,” Swanson said. “If you understand more about how these receptors signal at a basic level, then it allows people in drug development to think in new and different ways about targeting the activity of those receptors in order to achieve a beneficial effect.”

Swanson hopes future research will help understand whether this mode of signaling is unique to the synapses examined in the study, or whether the findings are to some extent generalizable throughout the central nervous system.