5-HT2A血清素 z-bo 2021-11-26 410

　　Hallucinogens such as lysergic acid diethylamide (LSD), psilocybin (psilocybin), and mescaline can cause severe and often long-lasting hallucinations, but they are used in the treatment of severe depression and other serious symptoms. Mental illness shows great potential. To fully study this potential, scientists need to know how these drugs interact with brain cells at the molecular level to cause their striking biological effects.

　　In a new study, Dr. Bryan L. Roth of the University of North Carolina at Chapel Hill and Dr. Georgios Skiniotis of Stanford University and their colleagues have taken a big step in this direction. They analyzed for the first time the high-resolution structure of these hallucinogens when combined with 5-HT2A serotonin receptor (HTR2A) on the surface of brain cells. The relevant research results were published in the journal Cell on September 17, 2020. The title of the paper is "Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor".

　　This discovery is already leading people to explore more precise compounds that can eliminate hallucinations but still have a strong therapeutic effect. In addition, scientists can also effectively change the chemical composition of drugs such as LSD and psilocybin. Among them, psilocybin is a hallucinogenic compound in mushrooms, which has been granted a breakthrough in the treatment of depression by the US Food and Drug Administration (FDA) Sexual status.

　　The co-corresponding author of the paper, Dr. Bryan L. Roth, professor of pharmacology at the University of North Carolina at Chapel Hill School of Medicine, said, “Millions of people take these drugs for recreation, and now they are gradually becoming therapeutic drugs. The first time I understand them How it works at the molecular level is really important. This is the key to understanding how they work. Given the remarkable efficacy of psilocybin on depression (in a phase II clinical trial), we believe our findings will accelerate the discovery Effective antidepressants, and it is possible to discover new drugs for other diseases such as severe anxiety and substance use disorders."

　　Scientists believe that the expression level of HTR2A in the human cerebral cortex is very high, and its activation is the key to the action of hallucinogenic drugs. Roth said, "When activated, this receptor causes neurons to fire in an unsynchronized and disordered manner, thereby inputting noise into the brain system. We think this is the cause of the psychedelic experience with these drugs. But currently It is completely unclear how these drugs exert their therapeutic effects."

　　In this new research, Roth's laboratory collaborated with Skiniotis, a structural biologist at Stanford University School of Medicine. Skiniotis said, "The combination of a number of different research advances has allowed us to carry out this research. One of them is the preparation of a better and more uniform 5-HT2A receptor protein. The other is cryo-electron microscopy (cryo-EM). , It allows us to observe very large complexes without having to crystallize them."

　　Roth praised Dr. Kuglae Kim, a postdoctoral researcher in his laboratory, because Kim has unswervingly explored various experimental methods to purify and stabilize the very fragile serotonin receptor HTR2A. Roth said, "Kim is amazing. I do not exaggerate to say that the work he has done is one of the hardest things to do. In three years, in a deliberate, repetitive, and creative process, he The serotonin protein can be slightly modified so that we can get a sufficient amount of stable protein for research."

　　The Roth team used Kim’s research work to reveal for the first time the X-ray crystal structure of LSD and HTR2A when combined. Importantly, Skiniotis and his team subsequently used cryo-electron microscopy to reveal the image of a prototype hallucinogen called 25-CN-NBOH combined with the entire receptor complex (including the effector protein Gαq). In the brain, this complex controls the release of neurotransmitters and affects many biological and neural processes. Kim used cryo-electron microscopy images to illustrate the precise structure of HTR2A at the amino acid level.

　　Roth and colleagues are now applying their findings to structure-based new drug discovery in order to develop new therapeutic drugs. One of the goals is to discover potential drug candidates that may provide therapeutic benefits without hallucinogenic effects.

　　Skiniotis said, "The more we understand how these drugs bind to HTR2A receptors, the better we can understand their signal transduction properties. This study has not provided us with a full picture, but it provides a significant part of it. "