6 March 2008. A complex between two very different neurotransmitter receptors, a serotonin receptor and a metabotropic glutamate receptor, might help elucidate the underlying pathology of schizophrenia, according to an advance online publication in the February 24 Nature. Researchers led by Stuart Sealfon and Javier González-Maeso at Mount Sinai School of Medicine, New York, report that the metabotropic glutamate receptor 2 (mGluR2)/5-hydroxytryptamine 2A receptor (2AR) complex elicits unique cellular responses when activated by hallucinogenic drugs, which mimic some of the symptoms of schizophrenia, and that the expression of these receptors is altered in the brains of people with the disorder. The findings lead the authors to conclude that “…this complex is therefore a promising new target for the treatment of psychosis.”
That the 2AR and mGluR2 proteins interact is not such a far-fetched idea since both are G-protein-coupled receptors (GPCRs), which are known to form heterodimers and even larger mixed oligomers. However, all such complexes found to date are between GPCRs of the same class (there are six classes in all). What is unique about the 2AR/mGluR2 complex is that the receptors belong to different GPCR classes, and the researchers provide convincing evidence for this unique arrangement.
First author González-Maeso and colleagues discovered the complex when studying the distribution of metabotropic glutamate receptors. They found that the 2AR receptor rarely colocalized with mGluR3 in the sensory cortex of mice, but interestingly, cells containing 2AR almost always test positive for the mGluR2 subunit. When they investigated further, they found that 2AR was essential for proper expression of mGluR2 in cortical cells—mice with disrupted 2AR expression showed reduced mGluR2 levels.
Given that the receptors turn up in the same place and seem to have a regulatory relationship, the researchers wondered if they might form a complex. González-Maeso and colleagues used a variety of methods to put that theory to the test. Using immunoprecipitation of human cortical samples and transfected cells, as well as two techniques that reveal if molecules are in close molecular proximity (bioluminescence resonance energy transfer and fluorescence resonance energy transfer), the researchers conclude that the proteins do form a complex.
But would such an entity be functional? The answer to that question appears to be yes, since the affinity of one receptor appears to depend on the other. For example, when the researchers used the non-hydrolyzable GTP analog GTP-γS to drive the receptors apart, affinities of each for their ligands dropped. Also, the glutamate receptor agonist LY379268 increased the affinity of 2AR for the hallucinogenic agents DOI, DOM, and DOB, whereas the hallucinogen DOI decreased the affinity of mGluR2 for its agonists. The researchers were able to abolish these allosteric interactions by using receptor antagonists.
Interestingly, the authors found that the mere presence of mGluR2 influences 2AR function by decreasing activation of the Gαq/11 subunit and increasing activation of the inhibitor Gαi subunit—these are components of G-protein signaling. These effects were reversed in the presence of mGluR2 agonists. Furthermore, glutamate agonists seem to modulate the effects of hallucinogens on 2AR receptor signaling in mice. Hallucinogens such as LSD can trigger two types of signaling through 2AR, one involving activation of the transcription factor c-fos and the other activating the transcription factor egr-2. Non-hallucinogenic 2AR agonists only activate c-fos. The researchers found that the glutamate agonist LY379268 had no effect on the c-fos pathway, but blocked the induction of egr-2, suggesting that the agonist specifically blocks only the hallucinogenic signaling that is propagated through the 2AR receptor. In fact, they also found that LY379268 can block head twitching movements in mice induced by hallucinogenic drugs. “Our results are consistent with the hypothesis that the 2AR-mGluR2 complex integrates serotonin and glutamate signaling to regulate the sensory gating functions of the cortex, a process that is disrupted in psychosis,” write the authors.
These findings offer new support for the idea that metabotropic glutamate receptor agonists may prove beneficial in schizophrenia. Glutamate signaling is reduced in the disorder and recent clinical trials suggest that mGluR agonists may be compensatory (see SRF related news story). There are indications, too, that mGluRs have an active role in learning and memory, which suggests that mGluR agonists may have the added benefit of correcting cognitive impairment associated with the disease (see SRF related news story). Now, González-Maeso and colleagues’ findings suggest that mGluR agonists could have an effect on hallucinations. In fact, when they examined postmortem brain samples from schizophrenia patients, the researchers found that the levels of 2AR and mGluR2 are increased and decreased, respectively, in membranes from the cortex. “Thus, the increased 2AR and decreased mGluR2 found in the brain in schizophrenia may predispose to a hallucinogenic pattern of signaling,” suggest the authors.—Tom Fagan.
Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez, JF, Zhou M, Okawa Y Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008 Feb 24; [Epub ahead of print] Abstract