Inner receptors may be important for fragile X treatment

Contrary to popular belief, receptors both outside and inside a cell regulate a cellular pathway that is overactive in people with fragile X syndrome, researchers reported Tuesday at the Society for Neuroscience annual meeting in San Diego. The finding could have significant implications for drug treatments of fragile X syndrome.

Inactivation of the fragile X mental retardation protein, or FMRP, leads to fragile X syndrome. Loss of FMRP leads to over-activation of a pathway controlled by a type of protein receptor called mGluR5.

mGluR5 receptors sit across membranes. They relay information by binding to a signaling molecule on one side of the membrane, leading to changes on the other. About 60 to 70 percent of mGluR5 receptors are on membranes inside cells, such as the nuclear membrane, but it’s unclear whether these receptors affect the same pathways as the cell-surface receptors do.

Several pharmaceutical companies are developing molecules that inhibit mGluR5 receptors as a treatment for fragile X syndrome. These molecules may not be able to get into cells to turn off the inner receptors, however.

“We really think people need to be aware of internal mGluR5 receptors,” says Karen O’Malley, professor of neurobiology at Washington University in St. Louis. “This could be an effect pharmaceutical companies are missing.”

In 2009, O’Malley’s team showed that internal mGluR5 receptors activate calcium signaling. The scientific community was hesitant to accept this idea. “People still tell us all the time, receptors only work at the cell surface,” says O’Malley.

The new study extends these findings to show that internal mGluR5 receptors activate the same pathways that are overactive in fragile X syndrome, and that drug treatments are attempting to block.

O’Malley says they are able to distinguish between receptors inside and outside the cell by using “fabulous tools”: a molecule that turns on mGluR5 receptors and can get into cells, and a molecule that turns off receptors, but cannot get into cells. When these two molecules are combined, only the internal receptors are activated.

The researchers show that activating internal receptors alone leads to two molecular features of fragile X syndrome: over-expression of activity-regulated cytoskeleton-associated protein, or ARC, and a decrease in the levels of another cellular receptor, AMPAR, at the cell surface.

The researchers are beginning to look at the effect of these intracellular mGluR5 receptors on neuronal projections, called dendritic spines, which are not fully formed in people with fragile X syndrome.

Understanding the different roles of the receptors can help scientists develop specific treatments for fragile X syndrome, O’Malley says. For example, targeting only the internal receptors might help avoid unpleasant side effects, she says.

O’Malley says she doesn’t know whether the mGluR5 receptor drug under development at Seaside Therapeutics targets both internal and external receptors. “They won’t give any to me, but I would love to test it,” she says.

For more reports from the 2010 Society for Neuroscience annual meeting, please click here.