A new study by Virginia Commonwealth University researchers suggests that dysregulation in the way two G protein-coupled receptors talk to each other may be responsible for some symptoms of schizophrenia and could lead to new treatment targets.
The study “Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia,” was published in the journal Science Signaling in January.
GPCRs are proteins that sense signaling molecules such as hormones and neurotransmitters and are the targets of many prescribed drugs. Healthy brain function relies on GPCR signaling, and alterations in this process can result in various diseases and ailments, including hypertension, diabetes and pain, as well as neurological and psychiatric disorders.
In this case, researchers analyzed the structure of two GPCRs involved in schizophrenia and antipsychotic drug action: serotonin 5-HT2A and glutamate mGlu2.
Until relatively recently, these GPCRs were assumed to function as monomeric signaling units. Monomers are proteins made up of a single polypeptide chain. In a 2008 study published in Nature by the same team, researchers discovered that these two GPCRs were actually assembled as heteromeric complexes, which contain two or more polypeptide chains, and are located in close molecular proximity at the cell surface. This structure functions in a different way than the monomeric complex and changes the way therapeutic drugs affect it, too. Building on that knowledge, researchers in the new study were able to characterize the mechanism for how 5-HT2A and mGlu2 crosstalk within the receptor complex and show that this crosstalk is altered in both lab mice and postmortem brain tissue samples of schizophrenic patients.
“We found that if you activate only the mGlu2 receptor in single cells expressing both mGlu2 and 5-HT2A, you have both Gi signaling and Gq signaling,” said Javier González-Maeso, Ph.D., associate professor in the Department of Physiology and Biophysics at the VCU School of Medicine. However, when you activate the mGlu2 receptor in animals without the serotonin 5-HT2A receptor, Gq signaling doesn’t occur. The brain tissue samples of schizophrenic patients indicated the same thing: Gi signaling but no Gq signaling.
Gi and Gq are molecules that control how each cell decodes the various signals coming from the GPCRs. Previous studies have shown that a specific ratio of Gi versus Gq signaling is necessary to induce antipsychotic responses in mouse models of schizophrenia.
“Our findings suggest that this crosstalk is changed in patients with schizophrenia and might be responsible for some of the symptoms,” González-Maeso said.
Knowing this, researchers can consider new therapies for schizophrenia. Current treatment addresses symptoms through drugs that target one receptor. Often, these drugs either do not work or patients have severe secondary effects. About 74 percent of patients end treatment, according to González-Maeso.
“With these new findings, we set the stage for new pharmacological approaches that will allow us to balance Gi and Gq signaling with the final goal of developing new therapeutic strategies for schizophrenia treatment,” González-Maeso said.
Schizophrenia is a mental illness that affects 1 percent of the U.S. population. The disease interferes with cognitive function, managing emotions and social interactions. Risk factors for schizophrenia include genetics, environment and brain chemistry.
González-Maeso’s collaborators include José L. Moreno, Ph.D., VCU Department of Physiology and Biophysics; Diomedes E. Logothetis, Ph.D., chairman of the Department of Physiology and Biophysics, VCU School of Medicine; and J. Javier Meana, M.D., Ph.D., Department of Pharmacology, University of the Basque Country.
Funding: The research was funded by the National Institutes of Health grant R01MH084894.
Source: Anne Dreyfuss – Virginia Commonwealth University
Image Credit: The image is credited to Marco Castellani and is licensed CC BY SA 2.0
Original Research: Abstract for “Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia” by José L. Moreno, Patricia Miranda-Azpiazu, Aintzane García-Bea, Jason Younkin, Meng Cui, Alexey Kozlenkov, Ariel Ben-Ezra, Georgios Voloudakis, Amanda K. Fakira, Lia Baki, Yongchao Ge, Anastasios Georgakopoulos, José A. Morón, Graeme Milligan, Juan F. López-Giménez, Nikolaos K. Robakis, Diomedes E. Logothetis, J. Javier Meana, and Javier González-Maeso in Science Signalng. Published online January 12 2016 doi:10.1126/scisignal.aab0467
Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia
Heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) can form multiprotein complexes (heteromers), which can alter the pharmacology and functions of the constituent receptors. Previous findings demonstrated that the Gq/11-coupled serotonin 5-HT2A receptor and the Gi/o-coupled metabotropic glutamate 2 (mGlu2) receptor—GPCRs that are involved in signaling alterations associated with psychosis—assemble into a heteromeric complex in the mammalian brain. In single-cell experiments with various mutant versions of the mGlu2 receptor, we showed that stimulation of cells expressing mGlu2–5-HT2A heteromers with an mGlu2 agonist led to activation of Gq/11 proteins by the 5-HT2A receptors. For this crosstalk to occur, one of the mGlu2 subunits had to couple to Gi/o proteins, and we determined the relative location of the Gi/o-contacting subunit within the mGlu2 homodimer of the heteromeric complex. Additionally, mGlu2-dependent activation of Gq/11, but not Gi/o, was reduced in the frontal cortex of 5-HT2A knockout mice and was reduced in the frontal cortex of postmortem brains from schizophrenic patients. These findings offer structural insights into this important target in molecular psychiatry.
“Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia” by José L. Moreno, Patricia Miranda-Azpiazu, Aintzane García-Bea, Jason Younkin, Meng Cui, Alexey Kozlenkov, Ariel Ben-Ezra, Georgios Voloudakis, Amanda K. Fakira, Lia Baki, Yongchao Ge, Anastasios Georgakopoulos, José A. Morón, Graeme Milligan, Juan F. López-Giménez, Nikolaos K. Robakis, Diomedes E. Logothetis, J. Javier Meana, and Javier González-Maeso in Science Signalng. Published online January 12 2016 doi:10.1126/scisignal.aab0467