A recent study led by the Hospital del Mar Medical Research Institute, in partnership with the Neuropsychopharmacology Group at the University of the Basque Country (UPV/EHU) and researchers from the CIBER of Mental Health (CIBERSAM), and published in Nature Communications, has revealed the involvement of two proteins in the process of activating and deactivating the mechanism by which drugs combat symptoms of schizophrenia. This discovery could potentially lead to the development of personalized treatments for individuals with schizophrenia. These individuals commonly experience a range of symptoms, including hallucinations, delusions, and disorganized thinking.
Symptoms of schizophrenia can include delusions, hallucinations, cognitive deficits, memory or language impairment, and depressive symptoms. Current treatments, which primarily target the type 2A serotonin receptor, are not able to specifically address the symptoms experienced by the patient. This often leads to side effects and issues such as metabolic or motor problems, ultimately resulting in patients discontinuing treatment.
The study has found that G proteins, a type of protein, play a crucial role in modulating cell responses in schizophrenia. Specifically, two types of these proteins were identified in this context.Proteins play a crucial role in managing the main symptoms of this disorder. According to Dr. Jana Selent, a key author of the study and head of the Drug Discovery Group focused on G protein-coupled receptors at the Hospital del Mar Medical Research Institute, these proteins are connected to the same receptor. However, they have different effects on the cells, leading to diverse reactions. This discovery is valuable for future research, as it can help in the development of personalized drugs for treating schizophrenia based on each patient’s specific symptoms.
Complex SituationThe researchers conducted in-depth research to reach their conclusions. They began by choosing several molecules that are not yet approved as drugs for humans and analyzing them at a molecular level through atomic-level simulations to see how they interact with the type 2A serotonin receptor. From this, they identified four compounds that were then tested in cells. These tests showed that when the compounds bound to the receptor, they elicited responses from various types of G proteins. The researchers also analyzed human brain tissue samples from the Neuropsychopharmacology G.The University of the Basque Country (UPV/EHU) has a collection of studies by the Integrated Pharmacology and Systems Neuroscience Group. According to Dr. Patricia Robledo, one of the principal authors of the study, the compounds in the collection had varied effects on G proteins. Some activated them, while others deactivated them. This led to the suggestion of inhibiting the coupling of the serotonin 2A receptor to certain G proteins as a potential area of interest for developing a new type of drug called inverse agonists, which could be useful in treating psychotic conditions. Rebeca also mentioned this as a significant finding.Diez-Alarcia, a researcher at UPV/EHU, was the first co-signer of the article. Additionally, in a mouse model that was created to mimic symptoms of schizophrenia, these compounds had different behavioral effects based on the G protein they activated. Through the use of pharmacological and genetic techniques in mice, it was discovered that one of these G proteins is linked to symptoms of psychosis, while another type of G protein is associated with cognitive deficits. Dr. Robledo emphasized that this is the first time that promising therapeutic targets have been identified for the development of drugs that can benefit specific profiles of schizophrenia patients.Even though the substances tested in the research are not yet authorized for human use, Dr. Jana Selent emphasizes that “this comprehensive study provides a blueprint for developing future medications that target specific pathways to treat schizophrenia, while avoiding pathways linked to side effects. This is highly important for a more personalized approach to treatment.”
Dr. Daniel Berge, a psychiatrist at the Mental Health Institute of the Hospital, who was not involved in the study, highlights that “this research will aid in the development of more targeted medications for treating schizophrenia, which could offer improved tolerance and greater accuracy in treatment.The disease’s symptoms could be better understood through this research. This understanding could lead to improved treatment adherence, ultimately preventing relapses and improving quality of life.” The study was financially supported by ERAnet NEURON, using European funds and competitive public funds from Spain, Germany, and Canada.
