How the ‘happy hormone’ is transported

How the ‘happy hormone’ is transported

There are tens of billions of neuron cells distributed in the human brain, and independent neurons are connected through “synapses”. But a question arises, how is information transmitted across synapses? German pharmacologist Otto Loewy cleverly designed the frog heart experiment, proving that stimulating the vagus nerve releases certain chemicals rather than electrical signals. Loewy later successfully isolated the substance, acetylcholine, and won the 1936 Nobel Prize in Physiology or Medicine together with Dell. This was the first neurotransmitter discovered in human history. Later, Swedish scientist Arvid Carlsson discovered another neurotransmitter, dopamine, and confirmed that insufficient secretion can cause Parkinson’s disease. He and two other scientists who explained synaptic transmission won the 2000 Nobel Prize in Physiology or Medicine. Since then, the mystery of neurotransmitters has been gradually unveiled, and so far it has been discovered that various substances including dopamine, 5-hydroxytryptamine, epinephrine, acetylcholine, amino acids, etc. can be used as neurotransmitters to regulate neural activity.

So, who helps with the transport of “happy hormones” in the brain? In the resting state of neurons, once neurotransmitters are synthesized, they are transported to vesicles and stored at high concentrations until a stimulus signal is received, causing vesicle release, thereby preventing sustained stimulation. There must be some substance on the vesicle membrane that can transport various neurotransmitters into the vesicle against the concentration gradient. In the 1970s, researchers identified a transporter protein located in the brain, responsible for transporting and storing neurotransmitters, and named it VMAT2. Over the past 50 years, the substrate preference and pharmacological properties of VMAT2 have been gradually reveal. VMAT2 belongs to SLC18, a member of the solute transporter 18 family. It can utilize the proton electrochemical gradient within the vesicle to promote substrate transport. It is estimated that each transport of a monoamine neurotransmitter requires the consumption of two protons. If the brain is compared to a city, material information transmission is carried out through “neuron highways”, and vesicles are trucks loaded with “neurotransmitter cargo”, then VMAT2 is equivalent to the “cargo crane” that comes with the truck. Consume the protons in the truck as “energy” to ensure efficient and rapid information transmission between cities.

Without VMAT2, trucks will run in vain or even go on strike, ultimately leading to insufficient neurotransmitter release and triggering a series of monoamine deficiency symptoms and diseases, including developmental delays, movement disorders, depression, Huntington’s disease and other diseases. The physiological significance of VMAT2 is so important. Exploring the structure and working mechanism of VMAT2 will promote the development of drug targets for various mental diseases.

Recently, Jiang Daohua’s team from the Institute of Physics, Chinese Academy of Sciences, and Zhao Yan’s team from the Institute of Biophysics used cryo-electron microscopy single-particle technology to analyze the high-resolution structure of multiple states of the monoamine transporter VMAT2, explaining in detail the transport of monoamine neurotransmitters. into vesicles.

Because VMAT2 is a membrane protein with a very small molecular weight and lacks a soluble domain, it is very difficult to analyze its structure using cryo-electron microscopy single-particle technology. In order to solve this problem, the research team screened fusion protein sites and fused other proteins with good stability into the extracellular region of VMAT2. They successfully obtained a VMAT2 fusion protein with increased molecular weight, stable properties, and rigid signals, which enabled structural analysis. The difficulty was greatly reduced, and finally the near-atomic resolution structure of VMAT2 combined with three different drug molecules and the substrate 5-hydroxytryptamine was successfully calculated and reconstructed through cryo-electron microscopy. Structural analysis shows that the obtained electron microscopy structure is in different conformations of cytoplasmic orientation, occluded state and vesicle cavity orientation, representing three typical conformations in the complete transport cycle of VMAT2. The three different conformations also represent possible differences in the inhibitory mechanisms of different drugs. For example, in the obtained structure, the VMAT2 structures bound by the three inhibitors reserpine, tetrabenazine, and ketanserin are all in different conformations. The resolved structure well illustrates the molecular mechanism by which three different drug molecules can stabilize the conformation of VMAT2 and block transport. When the substrate 5-hydroxytryptamine binds to VMAT2, VMAT2 is in a vesicle-oriented conformation, indicating that the substrate is about to be released.

According to experts, this research has greatly promoted the study of VMAT2 transporting monoamines, provided an important structural basis for understanding the molecular mechanisms of VMAT2 such as substrate recognition, drug inhibition, and proton-coupled transport processes, and provided a template for the development of better drug molecules. information. At the same time, the method used to analyze VMAT2 in this study can be applied to other small membrane proteins, which will facilitate the electron microscopy structure analysis of membrane transport proteins and other small proteins.

Although initial progress has been made, the research team wants to continue to delve deeper. For example, VMAT2 can recognize a variety of endogenous and exogenous substrates. Are their transport mechanisms common? How do protons participate in and drive protein conformational transitions during transport? These questions remain to be answered by researchers. (Author: Wu Di, PhD from Institute of Physics, Chinese Academy of Sciences)

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