Defining the Subcellular Specificity of Metabotropic Glutamate Receptor (mGluR5) Antagonists

With $109,500 in grants from FRAXA Research Foundation over 2008-2012, Dr. Karen O’Malley of Washington University studied the relationship between fragile X syndrome and mGluR5. Results published.

Karen O'Malley
$109,500 Grant
Karen O’Malley, PhD
Principal Investigator
Washington University
2008-2012 FRAXA Research Grant
$109,500 over 5 Years

Karen O’Malley’s team studyied the function of mGluR5 when it is inside cells. Conventional wisdom had been that mGluR5 is active only at the surface of neurons, but Dr. O’Malley has shown that mGluR5 also functions inside cells.  In fact, 90% of mGluR5 is in the interior of cells.

Many of the symptoms of fragile X syndrome (FXS) are thought to arise due to overactive metabotropic glutamate receptor 5 (mGluR5) signaling, which is normally opposed by the protein missing in FXS, fragile X protein (FMRP). mGluR5 is an important neuronal receptor that controls proteins involved in modifying synapses, which are the bridges by which neurons communicate with one another. Through its involvement in remodeling synapses, mGluR5 has been implicated as a key player in many neurological processes, such as learning and memory.

Although receptors like mGluR5 had been traditionally thought to initiate their signaling cascades from the cell surface, there was mounting evidence that intracellular receptors, located on membranes inside cells, were also physiologically active. However, studies of mGluR5 had focused solely on cell surface signaling, despite the fact that that up to 90% of mGluR5 is intracellularly located. To remedy that, our research concentrated on discovering the properties and functions of intracellular mGluR5 as compared to cell surface mGluR5. In additional, it was also essential to test the permeability of mGluR5 antagonists in order to determine whether they were acting at the cell surface mGluR5 alone or if they reached the inside of cells as well. By analyzing the roles of intracellular and cell surface mGluR5 in FXS and determining the permeability properties of mGluR5 antagonists, we hoped to achieve increased specificity in targeting drugs to the appropriate cellular locations and thus improved treatment of FXS.

Results:

March 2014

Researchers led by Dr. Karen O’Malley at Washington University School of Medicine in St. Louis published results of their work on mGluR5 and Fragile X syndrome. FRAXA Research Foundation provided funding for this work from 2009 until 2013.

Pharmaceutical companies have developed therapeutic compounds to decrease signaling associated with the mGlu5 receptor, moderating its effects on brain cells’ volume controls. But the compounds were designed to target mGlu5 surface receptors. In light of the new findings, the scientists question if those drugs will reach the receptors inside cells.

“Our results suggest that to have the greatest therapeutic benefit, we may need to make sure we’re blocking all of this type of receptor, both inside and on the surface of the cell,” said senior investigator Karen O’Malley, PhD.

Press Release from Washington University

Carolyn Ann Hogan
Graduate Student
2010-2011

Vikas Kumar, PhD
FRAXA Postdoctoral Fellow
2008-2009