Pengpai News reporter He Liping
Where is the source of human happiness coming from? In the eyes of scientists, serotonin, dopamine and endorphins are the three most important substances. Among them, serotonin (5-HT), or serotonin, is an important neurotransmitter that plays a role in the brain and gives us the ability to feel happiness and happiness, also known as the "happy neurotransmitter".
Past studies have found that serotonin is involved in a wide range of physiological functions of the human body, including regulating the brain's memory, cognition, emotion, learning and addictiveness. Illegal system disorders may cause a variety of mental diseases, such as depression, schizophrenia, bipolar disorder, bipolar disorder, , migraine, etc. But how does serotonin make people feel happy? This biological mechanism has never been deciphered.
In the early morning of March 25, Beijing time, the top academic journal Nature published an online study jointly completed by researchers from the School of Basic Medicine of Zhejiang University, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and other teams, entitled "Structural insights into the lipid and ligand regulation of serotonin receptors". This study reported for the first time internationally the near-atomic resolution structure of three 5-hydroxytryptamine receptors , revealing how phospholipids and cholesterol regulate receptor function, as well as the molecular regulatory mechanism of the antidepressant drug aripiprazole (Aripiprazole).
The corresponding authors of this paper are Researcher Zhang Yan from the School of Medicine of Zhejiang University, Liangzhu Laboratory, Medical Center, Researcher Zhang Yan from the Shanghai Institute of Materia Medica Researcher Xu Huaqiang and Researcher Jiang Yi. Zhang Huibing, a doctoral student at the School of Basic Medicine of Zhejiang University, and Mao Chunyou, a postdoctoral student at the Shanghai Institute of Pharmaceuticals and Zhejiang University School of Basic Medicine, Xu Peiyu, a doctoral student at the Shanghai Institute of Pharmaceuticals and Shanghai University of Science and Technology, Huang Sijie, a doctoral student at the Wen Anluo Institute of the United States, and an associate researcher at the Shanghai Institute of Pharmaceuticals and Cheng Xi, an associate professor at the Shanghai Institute of Pharmaceuticals and Pharmaceuticals.
In the report of this study, Zhejiang University mentioned that serotonin must be mediated by the corresponding receptors in order to act. The receptors have more than a dozen different subtypes in the human body, including serotonin receptors 1A, 1B, 1D, 1E, etc., which are distributed in different brain regions and mediate excitatory and inhibitory neurotransmission.
As of now, serotonin receptor 1A is the most concentrated receptor subtype targeted by clinical drugs, and is the main drug target of aripiprazole, a drug for clinical treatment of schizophrenia and depression. Serotonin receptor 1D has high sequence homology with serotonin receptor 1B and is also a target of action for triptan anti-migraine drugs; serotonin receptor 1E is related to memory. In addition, even if the brain does not secrete serotonin to activate its receptors, the body will maintain a certain sense of happiness.
It is worth mentioning that scientists still have little knowledge of the fine structure of serotonin family receptors, so the development of neurologic drugs is also relatively extensive. Although it can produce positive effects, a series of side effects are followed. Taking anti- schizophrenia and antidepressant drugs as examples, patients usually experience symptoms such as drowsiness and weight gain after taking it. Cryoelectron microscopy structure of
5-HT1A, 5-HT1D and 5-HT1e receptors with ligands and Gi protein complexes.
In order to develop more effective therapeutic drugs with lower toxic side effects, the research team used single-particle cryoelectron microscopy technology to analyze the cryoelectron microscopy structures of the above three serotonin receptors binding to different ligands for the first time.
5-hydroxytryptamine receptor is a protein located on the cell membrane. In addition to endogenous ligands and drug molecules that can regulate their functions, lipids also play a crucial regulatory role in maintaining the normal function of the receptor. This study breaks through many technical difficulties and reports for the first time internationally that the molecular regulatory mechanism of 5-HT1A receptors subject to phospholipids and cholesterol. Phospholipid and cholesterol regulation of
5-HT1A receptor.
study found that the phospholipid molecule PI4P can bind to the interaction interface between the 5-HT1A receptor and the G protein . Multiple cholesterol molecules bind to the transmembrane region of the receptor and directly participate in the activation of the receptor.
research team also conducted research on aripiprazole, a third-generation schizophrenia therapeutic drug that can activate serotonin receptor 1A.They found that when serotonin and aripiprazole deactivate the 5HT1A receptor, the latter reacted more slowly after pulling the "happy production" trigger.
"We also revealed the structural and efficacy relationship of the drug action under different receptors, clearly showing why aripiprazole has the ability to activate serotonin receptor 1A and is nearly 100 times stronger than that of 1D or 1E, and explaining why serotonin is a master key that can activate many different serotonin receptors at the same time." Zhang Yan said.
study believes that these structures provide an important basis for drug development targeting serotonin receptors. "We often say that if a key opens a lock, we must first understand what the lock core looks like." Zhang Yan believes that in the past, drug research and development often required luck to screen, and now design can be carried out through the deconstruction of the lock core. "In the future, with the continuous deepening of research, the development of antidepressants with better efficacy and fewer side effects with one key, will no longer be just a dream."
Paper link: https://www.nature.com/articles/s41586-021-03376-8.pdf
Editor: Li Yuequn
Proofreading: Luan Meng
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