Tuchong Creative Our emotions and physical activities rely on the regulation of chemical messengers in the brain called neurotransmitters. Norepinephrine is an important neurotransmitter that is responsible for getting the brain and body into an active state. Excessive transmission of nerve signals may lead to emotional instability, inattention and other problems. Therefore, excess norepinephrine needs to be recovered in time after being released from neurons. The norepinephrine transporter is responsible for this process. As an important molecule for maintaining brain stability, its working principle and structure have been unclear. Recently, Wu Jingxiang's team at the Institute of Materia Medica, Chinese Academy of Medical Sciences, used cryo-electron microscopy to reveal for the first time the morphological structure of the human norepinephrine transporter in different working states, laying an important foundation for in-depth research on its working mechanism and achieving artificial regulation. The relevant results were published in the journal Nature on August 14, 2024. When you mention norepinephrine, you may immediately think of adrenaline. Their chemical structures are similar, but norepinephrine has one less methyl group than adrenaline. Adrenaline is mainly secreted by the adrenal medulla and acts on the heart, blood vessels, and bronchi, etc., helping the body to enhance its ability to move in emergency situations, such as increasing heart rate and blood flow when rescuing patients; while norepinephrine is mainly secreted by sympathetic postganglionic neurons and noradrenergic neurons in the brain, and mainly plays a role in the central nervous system, regulating emotions, attention, and reaction speed. When the body is under stress, adrenaline and norepinephrine work together: the former enhances the body's athletic performance, and the latter ensures that the brain can react quickly, allowing the body and brain to better cope with challenges. Neurotransmitters are released from the synaptic site at the end of a neuron and are received by the receptors of the next neuron, thereby achieving signal transmission. The released neurotransmitters need to be removed in time, otherwise it will cause overexcitement of the brain and cause various disorders. For example, dopamine is a neurotransmitter associated with pleasure and pleasure. Drugs such as cocaine prevent dopamine from being recycled, allowing it to stay in the synaptic cleft longer1, resulting in excessive pleasure experience and ultimately addiction. Similarly, if excess norepinephrine is not removed in time, it may lead to overactivation of the sympathetic nerves, abnormal stress response, and even tumors in the nervous system. The norepinephrine transporter is the molecule responsible for this recycling work, which can recycle about 90% of norepinephrine from the synaptic cleft to the upstream neurons, ending its signal transmission. This is crucial for maintaining the balance of the nervous system. Clinically, norepinephrine transporter substrate 2 and inhibitors have been widely used. For example, iodine-131 methyl iodobenzylguanidine has been used as the gold standard for radiopharmaceutical imaging for many years to treat various tumors such as neuroblastoma. Inhibitors of the norepinephrine transporter slow down the recycling of norepinephrine, increase alertness and improve mood, and are used to treat diseases such as attention deficit hyperactivity disorder, narcolepsy and depression. Although it has been applied in clinical practice, questions such as the molecular structure of the human norepinephrine transporter, the way it transports substrates, and the principle of inhibition have not been clearly answered, which limits the progress of structure-based drug optimization and new drug design. A team from the Institute of Materia Medica, Chinese Academy of Medical Sciences, successfully revealed the structure of the human norepinephrine transporter in the unbound state, the bound state with the substrate, and the bound state with the inhibitor using cryo-electron microscopy technology. Cryo-electron microscopy is a cutting-edge structural biology technology that preserves the natural structure and state of biological macromolecules by rapid freezing, and then uses images taken with a high-resolution electron microscope to analyze the three-dimensional structure of biological molecules. Since the protein of the human norepinephrine transporter is small in size, lacks prominent structural features, and has an asymmetric structure, it is not conducive to imaging comparison. To solve this problem, the research team innovatively introduced a polypeptide tag containing 12 amino acids into the ring structure of the transporter, which not only increased the molecular weight and identification characteristics of the sample, but also played an auxiliary positioning role in the alignment of electron microscope images, thereby greatly helping the analysis of the structure. The study found that the structure of the human norepinephrine transporter is very similar to that of other neurotransmitters such as dopamine, serotonin and glycine. However, its unique substrate binding site makes it particularly good at recognizing and binding norepinephrine, thus ensuring highly specific uptake of this neurotransmitter. Radafaxine, an atypical antidepressant originally discovered as a metabolite of the antidepressant bupropion, has been shown to occupy a central position in the protein that the transporter uses to bind to substrates, thereby achieving its inhibitory effect by blocking the protein's structural transition. These research results not only provide a solid foundation for our in-depth understanding of the operating mechanism and dynamic changes of human norepinephrine transporters, but also provide valuable references for the development of targeted new drugs. In addition, we can also see the importance of structural biology in modern medical research. By exploring physiological and pathological mechanisms and the possibility of treatment at the molecular level, it is expected to promote revolutionary progress in disease treatment. This article is a work supported by the Science Popularization China Creation Cultivation Program Author: Xu Sijia, M.D., Kyoto University School of Medicine Reviewer: Tao Ning, Associate Researcher, Institute of Biophysics, Chinese Academy of Sciences Produced by: China Association for Science and Technology Department of Science Popularization Producer: China Science and Technology Press Co., Ltd., Beijing Zhongke Xinghe Culture Media Co., Ltd. |
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