|Studies of mGluR5 in Fragile X
By Karen O'Malley and Vikas Kumar, 6/1/2008
Typically G-protein coupled receptors such as the metabotropic glutamate receptor, mGlu5, are activated by contact with their neurotransmitters at the cell surface. Although receptors are also found within the cell they are presumed to be receptors that have just come off the cell surface or receptors poised to be inserted into the membrane if needed. Interestingly, however, a number of receptors have been found that can move from the cell surface all the way into the nucleus and there are other receptors that seem to be primarily expressed within the cell. What are these intracellular receptors doing? Is it the same function as the cell surface receptors? How are their neurotransmitters reaching them? What are the signals that send these receptors to different sites within the cell? Are there special proteins that hold intracellular receptors in place? And, importantly for various human diseases, can we design drugs that will target separate populations of receptors i.e. just the cell surface versus cell surface or just intracellular?
These are a few of the questions we have been focusing on in the last few years using mGlu5 as a model. To date, we know that in mGlu5-expressing striatal neurons, activation of intracellular receptors can lead to a much more robust and longer lasting signaling response than cell surface receptors. We know that the neurotransmitter can reach intracellular receptors using well-known transporter proteins. We also know that neurotransmitter activation of intracellular receptors can activate overlapping as well as distinct signaling systems within the neuron leading to the activation of distinct target genes. One differentially activated target gene in striatal neurons is the fragile X protein, FMRP.
As first described by Drs. Bear, Huber and colleagues, the mGlu5 receptor theory of fragile X syndrome theorizes that activation of mGlu5 is normally balanced by FMRP suppressing its responses. In fragile X syndrome, this balance is lost, leaving mGlu5 function unchecked. In most of these studies mGlu5 receptors are activated by the agonist, DHPG. Interestingly, DHPG is one of the drugs that we have shown can not cross the cell membrane. Thus DHPG only activates cell surface receptors. In vivo, however, it is glutamate release that activates receptors and glutamate can cross the cell membrane to activate intracellular receptors too. Therefore, our proposal is to test the idea that activation of cell surface versus intracellular receptors leads to differential changes in measures relevant to fragile x syndrome such as protein synthesis, AMPA receptor internalization and FMRP synthesis and localization. Results from these studies would further support our findings that depending upon their ability to cross cellular membranes, agonists and antagonists have differential effects on cell surface versus intracellular receptors. Most importantly, ligands might be tailored for even more selective applications based on the cellular distribution of the receptor.