drawing | Wang Ruonan
2021 Nian Nobel Prize in Physiology or Medicine winner
University of San Francisco professor California David Julius
Figure source: physiology.ucsf.edu
2021 Nobel Prize in physiology or Medicine Winner
Scripps Research Professor Ardem Patapoutian (Ardem Patapoutian)
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▼The Caroline School of Medicine in Sweden announced that the 2021 Nobel Prize in Physiology or Medicine will be awarded to professors from the University of California, San Francisco (UCSF) David Julius and Scripps Institute’s Ardem Patapoutian , reward them for their discovery of temperature perception and tactile receptors.
In 2020, "Intellectuals" reported that two scientists had won the Coveli Prize and they were reissued today. Attached "Intellectuals" special article, combing the process of David Julius' discovery of Trp ion channels and the current research status in this field.
author | Xin Ling
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nerve perception The secret of temperature and pressure
David Julius of the University of California, San Francisco and Adem Pataptian of the Scripps Institute have discovered human perception in their own independent studies The molecular mechanisms of temperature, pressure and pain,It provides an important basis for the research of physiological diseases related to touch.
The molecular receptors that sense external stimuli are the biological basis of the five human sensory systems. Although we have discovered molecular receptors related to vision and smell for a long time, the sense of touch, including the human body’s perception of temperature (warm and cold), mechanical force (such as shaking hands), and harmful substances (such as pain caused by eating hot peppers) It is always a mystery.
biologist Rao Yi once wrote an article (see Rao Yi: records of domestic doctors). In the 1980s, Julius began to use the then relatively new method to express the receptor for serotonin. More than ten years later, he continued to use this method to find receptors for capsaicin (a compound in pepper that can cause burning pain), and in 1997 he found a capsaicin-activated protein molecule VR1, Moreover, it was found that VR1 can be activated by heating, because capsaicin is known to be related to the pain pathway, so this work also uncovered the mechanism of temperature perception and part of the mechanism of peripheral pain perception. In this 1997 article, Julius also confirmed that VR1 belongs to the TRP channel family, and the TRP gene was first discovered in Drosophila as early as 1969, but people have never known its function. Therefore, Rao Yi commented that although Julius is not the first scientist to discover the TRP gene, he discovered that the protein encoded by the TRP gene plays an important role in the sensory system (temperature, pressure, etc.). "He (Julius) and Ardem are combined because they both contribute to the feeling of pressure. Among them, they and others have directly or indirectly contributed to the long-standing hearing." Rao Yi said.
School of Pharmacy, Tsinghua University researcher Xiao Bailong told Intellectuals,Julius' team later discovered other receptors in this family, such as the cool receptor and the mustard oil receptor. This newly discovered TRPV1 and related channels have now become the target of attention in the research and development of new analgesics.
"David Julius' work is very systematic, from the discovery of peripheral pain receptors to its structural and functional relationships, including the physiological knockout of by . Technology to study other receptors is a series of work. I think it is well deserved that David Julius won the award." Li Yulong, a researcher at the School of Life Sciences, Peking University, commented.
Pataptian and Julius are studying the problem of tactile receptors almost simultaneously. After discovering cool (menthol), mustard oil , and warm receptors, Pataputian decided to attack the more challenging mechanical force receptors. The study of mechanical force is extremely difficult. First, it is necessary to find a suitable stimulation method, and second, it is difficult to record the current generated.
Postdoc Bertrand Coste of Pataptian’s group found a glioma cell line that can grow in a laboratory dish. These cells respond by generating electrical signals. The pressure change brought about by the touch. Then, from more than 20,000 human coding genes, more than 300 candidate genes that are highly expressed in this kind of cells are carefully selected, and then cells that lack (knock down) these genes one by one are cultivated. Then the samples were tested one by one, looking for genes that would cause the cells to lose the induced current when they were missing. After more than three years of unremitting efforts, it was finally determined that the No. 72 candidate gene on the list has this function. They named this gene PIEZO,In Greek it means pressure. PIEZO exists in both animals and plants, and is highly conservative in evolution, suggesting that it is very important in function.
Dr. Xiao Bailong, who was engaged in post-doctoral research in the Pataptian group at the same time, witnessed this exciting discovery process and proved in subsequent studies that the PIEZO protein forms a new class of protein Pressure sensitive ion channel. Xiao Bailong pointed out: "The process of searching for stress receptors is full of risks. The candidate gene list may be incomplete, and technical problems may occur in the knockout process. However, persistent efforts have finally yielded this milestone scientific discovery."
Pataptian quickly confirmed that PIEZOs are essential genes for pressure sensing in mammals. His research has shown that PIEZOs can form ion channels , which are directly responsible for Merkel cells and tactile terminals in the skin, and proprioceptors (sensory nerve endings located in the muscles that can feel the body Position, posture and movement in space and react to pressure).
PIEZOs can also sense pressure through nerve endings distributed in blood vessels and lungs, and affect the volume of red blood cells, vascular physiology, and cause a variety of human genetic diseases. The discovery of PIEZOs opened the door to mechanobiology, an emerging scientific field that intersects biology, engineering, and physics. It focuses on the study of how the physical forces and mechanical properties of cells and tissues affect health and diseases. Influence.
"Ardem is an extremely smart and forward-looking scientist,But he is never satisfied with existing achievements, he is constantly exploring and full of desire for innovation. He has full trust in the researchers of the research group and always fully supports them to explore cutting-edge scientific issues. It is true that he won the Coveli Award for his discovery and research of the PIEZO channel. Xiao Bailong said.
"The two winners have made systematic and landmark contributions in the study of the molecular mechanism of peripheral perception. This award is well deserved. Li Yulong said. He believes that their awards once again show that excellent basic science requires time accumulation and curiosity, and these are the directions that Chinese scientists are actively working on.
Note: On An excerpt from an article in "Intellectuals" in 2020: 7 scientists won the Coveli Prize, but the award ceremony will be in 2022.
Attached: TRP channel past and present _span _strong27 author | Qi Xin Li Jie Lu Jianfei review | Tian-Le Xu Zhu Xi Li Haitao Zebian | Chenxiao Xue ● ● ● br145span br145span cell-dependent signal transduction of span cells.Among them, ion channels play a key role in real-time sensing of signals inside and outside the cell and regulating adaptive changes. In 2003, Peter Agre and Roderick Mackinnon won the Nobel Prize in Chemistry for discovering water channels and explaining the principle of ion selectivity for voltage-gated potassium channels.
The transient receptor potential we introduced today (Transient receptor potential, TRP) channel has also attracted generations of scientists with its complex regulation mechanism and rich physiological functions It's hard to explore.
1 our research
a windfall
compared to the voltage-gated ion channels, for TRP The channel research started late.
1969, D. J. Cosens and Aubrey Manning of the Department of Zoology, University of Edinburgh, UK, used ethanesulfonate on Drosophila melanogaster _span5 _span_span.EMS) was used as a mutagen, and a mutant was screened by artificial mutagenesis. This strain had abnormal phototaxis and retinal potential. Continuous light stimulation only caused short-term negative retinal potential, rather than common continuous, plateau-like changes. , And can not produce an effective response [1] when the second light stimulus comes.
University of California, Berkeley Gerald Rubin's postdoc Craig Montell later discovered that this was caused by a mutation similar to an ion channel membrane protein in Drosophila melanogaster, so they The gene was cloned first, and the protein was named transient receptor potential (TRP) channel [2] . The wild-type TRP channel mediates a light-activated continuous platform current in insect visual cells. The same channel does not exist in vertebrates, but there are many channel proteins that are evolutionarily related to the original Drosophila TRP channel, forming a protein superfamily.
TRP based on Drosophila was the first to be discovered. All superfamily members are named after TRP and are classified into TRPC (Canonical) _spanillo5span (VTRPVidspan), VTRPVidspan (VTRPVidspan), , TRPM (Melastatin) , TRPA (Ankyrin) , TRPP (Polycystin) , TRPML (Mucolipin) (Mucolipin) (Mucolipin) (Mucolispan) _NOMP-span5 (Span8)Among them, TRPN is only found in invertebrates, and the original Drosophila TRP belongs to the TRPC subfamily.
Figure 1 TRP channel subfamily[3] _span8 pspan5 _span8 pspan 0 Generation and regulation, with TRPV1 as the main representative. For a long time, people have known that pepper extract selectively activates the nociceptive neurons of the dorsal root ganglion (Dorsal root ganglion, DRG) , and induces them to produce action potentials [4] , which transmits noxious stimuli Produce pain to the central nervous system system. But by what mechanism does the stimulating molecule capsaicin activate neurons?
In order to screen the receptors that bind to capsaicin, a team led by Professor David Julius of the University of California, San Francisco in 1997 extracted more than 16,000 kinds of mRNA from rat DRG and divided them into different types. The components were transferred into tool cells to test their response to capsaicin, and the capsaicin receptor VR1 was successfully cloned. Analysis of VR1 protein sequence indicated that VR1 belongs to the TRP protein superfamily, so it was named TRPV1 channel [5] .
This gene encodes a 6-pass transmembrane protein, and the channel exhibits a high degree of calcium ion permeability of . TRPV1 can be specifically activated by capsaicin, and it can also be activated by high temperatures above 42°C, which not only confirms the principle of capsaicin activating sensory neurons, but also links pain and temperature perception together for the first time, revealing The molecular mechanism of why people feel spicy and hot at the same time when people eat chili.
So far, more than 50 TRP channels have been discovered in yeast, insects, fish and mammals. Although they belong to the TRP superfamily, their sequence identity does not exceed 20%. At the same time, there are huge differences in channel characteristics. Some TRP channels are expressed on the plasma membrane, integrating information inside and outside the cell, and mediating non-selective cation influx; Some are distributed on the organelle membrane, regulating the release of intracellular Ca2+ [6] . To understand the channel opening mechanism and physiological function, it is imperative to analyze their fine structure. 2
cryo key technological revolution detonated structural analysis
breakthrough
gene homologous to the Drosophila trp Highest sex,One of the first mammalian TRP channels whose full length has been analyzed is TRPC3. TRPC3 is widely expressed in the nervous system and heart. It is activated by second messengers such as diacylglycerol (diacylglycerol, DAG) , which senses the depletion of cytoplasmic calcium stores, opens and mediates non-selective cation currents, and participates in growth cone guidance. , Synaptic plasticity, vasoconstriction and other multiple physiological processes.
In 2007, Chikara Sato and others co-reported the cryo-EM structure of TRPC3, which is also the first full-length mammalian TRP channel structure to be resolved [7] . The electron microscope structure shows that TRPC3 is composed of four subunits. The entire channel forms a nested structure, which is composed of a spherical cavity in the middle and a discontinuous shell. When the channel is open, ions enter the cavity through the pores. The four openings at the bottom of the body flow into the cell. The different domains separated on the outer shell may also participate in the fine regulation of the gating mechanism.
The TRPV1 channel is followed by the full-length analysis. In 2013, Professor David Julius and Professor Yifan Cheng, a Chinese scientist from the same institution, published two consecutive articles in the journal " Nature", analyzing the closed and open structures of the full-length TRPV1, this It is the first membrane protein structure obtained by cryo-electron microscopy with an ultra-high resolution of nearly 3Å, which has greatly promoted the understanding of the molecular structure of TRP channels, and created a cryo-electron microscopy to study protein structure and protein-protein interactions. New era ,It also promoted the technology of cryo-electron microscopy to win the 2017 Nobel Prize in Chemistry .
Figure 2
Fig. The researchers found that the channel has a similar structure to the voltage-gated ion channel: TRPV1 is a tetramer, and each subunit has six transmembrane alpha helix domains, of which the 5th and 6th transmembrane domains Together they constitute the channel hole area, and the first 1-4 transmembrane domains constitute the voltage sensing site and the capsaicin binding site [8] . In the presence of resin toxic alkali (capsaicin analogue) and spider toxin DkTx, the open structure of TRPV1 can be obtained. By comparing its open and closed structures, it is found that TRPV1 has a unique two-door channel The activation mechanism (Figure 3) [9] , although it is still controversial whether its selective filter constitutes the upper gate that can really control ion flow. This work perfectly explained the opening principle and conformational changes of the TRPV1 channel under the activation of two different ligands of capsaicin and proton, but it also brings us new questions about whether temperature-mediated TRP channel opening is also specific What is the basis of structural biology?
FIG. 3 TRPV1 dual-gated channel gating mechanism [9]
3
Chunjiang plumbing "TRP" Know
In addition to being activated by ligands,Temperature sensitivity is also an important feature of the TRP family. We collectively refer to the TRP family members like TRPV1 that are open at a specific temperature as ThermoTRP.
So far, 11 ThermoTRPs have been identified in mammals, including the thermal receptors TRPV1-TRPV4 and TRPM2-TRPM5, and the cold receptors TRPM8, TRPC5, and TRPA1. These ThermoTRP can feel the temperature in the whole physiological range, from the burning heat that produces pain, to the comforting warmth and coolness, to the biting cold.
In addition, ThermoTRP can also be activated by chemical ligands, including the capsaicin just mentioned, as well as allicin, cannabinoids, mustard oil, menthol, cinnamaldehyde, etc. (Figure 4) [11] .
Figure 4 ThermoTRP and its chemical ligands 5 p0span5 and its chemical ligands 5 p0span5
5
, Has conducted a long-term exploration of the mechanism of how temperature activates ThermoTRP channels. The temperature represents the average kinetic energy of the microscopic particles in the region ,The thermal conductivity of will affect the particle arrangement. For peptide chain and protein, temperature changes will not only affect the polarity of amino acid residues, but also greatly change the conformation of the protein. It is this way of multi-modal participation that hinders the process of analyzing the temperature activation mechanism of ThermoTRP. At the same time, the temperature sensitivity of different species is different. For example, the activation temperature threshold of rat rTRPV1 is ~42℃, while the activation temperature of vampire bat (Vampire bat) TRPV1 is about 30℃, which increases the identification temperature. The challenge of the sensing domain.
For TRPV1, the regions currently identified to participate in temperature gating mainly include the N-terminal, C-terminal, outer pore area, and pore area (Figure 5) .
The anchored repeat domain at the N-terminus (Ankyrin repeat domain, ARD) determines the heat tolerance of thirteen striped ground squirrels and bactrian camel ground squirrels. derived from sqTRPV1 channel 190th aspartic acid is replaced with rat-like serine, which will mediate the increase of sqTRPV1 heat sensitivity, but does not affect its capsaicin and acid-induced chemical activation of [12] . Experiments have shown that the N-terminus connecting ARD and the first transmembrane segment is also called (Membrane proximal domain,MPD) and are used as temperature sensors to mediate the temperature sensitivity of TRPV1, and determine the energy changes and temperature sensitivity characteristics of the TRPV1 channel switching process under temperature stimulation. Use molecular biology to change this area into channels such as rTRPV2, hTRPV2, or mTRPV4, which not only converts the temperature-insensitive subtypes into temperature-sensitive channels, but also changes the temperature-sensitive characteristics of the wild-type channels It has to be the same as the TRPV1 channel [13] .
In addition, the endogenous intracellular agonist phosphatidylinositol (Phosphatidylinositol-4,5-bisphophate, PIP2) also affects the C-terminus of the channel and the distal and proximal membrane regions. Both are important modules [14,15] for sensing temperature stimulation. Exchanging the C-terminus of heat-activated TRPV1 and cold-activated TRPM8 can exchange its temperature sensitivity. In particular, the introduction of the two amino acid residues of TRPV1 Q727 and W752 into the wild-type TRPM8 channel can make it directly exhibit heat-activated It has characteristics and is not coupled with PIP2 activation, which shows that temperature sensing is different from the traditional ligand activation-dependent mechanism [16] .
Figure 5 TRPV1 temperature-sensitive domain [8] _span8pspan_br14p _span0 pbr14p _span0The two intracellular regions of the N-terminal and the C-terminal also mediate the thermal inactivation of TRPV1 through interaction [17] . In addition to the intracellular region, the channel pores and the peripheries of the pores also participate in temperature-sensitive regulation. The key sites, including C617 and C622 located in the channel pore area, and N628, N652, and Y653 located outside the pore area, will all have a significant impact after mutation. The temperature sensitivity of TRPV1 [18,19] . Each species has the most suitable temperature for survival, and the evolutionary pressure makes the TRP channel show significant species differences, which also demonstrates the importance of the TRP family for biological adaptation to environmental changes.
4 to shield Spear Against His because of its wide range of biological functions
and The flexible open mechanism, targeting TRP channel for clinical intervention has broad application prospects.
Taking TRPV1 as an example, it is a very transformative analgesic target [20] . As a sensor that converts nociceptive stimuli into electrical signals, the TRPV1 channel can also cause neuropathic pain (Figure 6) [21] when the sensory nerve endings are over-activated.For example, cancer patients sometimes suffer from severe peripheral neuralgia after chemotherapy, which cannot be completely relieved by conventional analgesics. This may be because cisplatin, oxaliplatin and paclitaxel and other chemotherapeutic drugs promote the function of TRPV1, which causes increased channel expression levels, channel sensitization, and oxidative stress response, which induces mechanical and thermal And cold hyperalgesia reaction [22] . Drugs that target the TRP channel can effectively alleviate the serious adverse reactions that cancer patients suffer from during chemotherapy. For example, resin toxicine can act as a "molecular scalpel", by specifically activating its receptor TRPV1 channel, causing calcium influx and calcium overload in the pain-receiving neurons expressing TRPV1, which in turn leads to the apoptosis of these neurons, as a chronic Cancer pain control means [23] .
Figure 6 ThermoTRP and pain are also the targets of the respiratory system span_p14p _span5 _span5 _span0 It is widely expressed in immune cells and structural cells in the lung, and plays a central role in causing respiratory symptoms such as bronchospasm and cough
In addition, targeting the TRP family, especially the TRPM subfamily, to intervene in neurological diseases also has clinical transformational significance. TRPM2 inhibitor JNJ-28583113 can significantly alleviate the oxidative stress damage of neurons in the process of ischemic stroke in mice [27] , and TRPM4 subunit not only promotes N-methyl-D-day N-methyl-D-aspartic acid receptor (N-methyl-D-aspartic acid receptor, NMDAR) membrane transport, aggravates the per-synaptic NMDAR-mediated neuronal death [28] , and can also interact with sulfonylurea receptor 1 (Sulfonylurea-receptor 1, SUR1) forms a complex to increase the permeability of the blood-brain barrier. The swelling leads to more serious nerve damage [30] .Exogenous glibenclamide targeting SUR1-TRPM4 heteromers to intervene in ischemic stroke has entered the third clinical stage. This further illustrates the application prospects of targeting TRP channels to intervene in central nervous system diseases.
TRP channel research continues, this is not only us understand how the body perceives external stimuli (temperature, pressure, injury stimuli) strong22 is also a highly inspiring and continuous target exploration epic. Its structure-to-function research paradigm has had a profound impact on the subsequent research of membrane protein . The progress and innovation of clinical medicine are inseparable from the exploration and discovery of basic science. We hope that as we deepen our understanding of TRP channels and other membrane proteins, we can truly reveal the mystery of biological evolution and generate more enlightening and clinically transformative values. Research results.
Note: This article is from the public part number "ion channel research progress"
Author
"
Qi Xin is Shanghai Jiao Tong University School of Medicine third-year doctoral student,Li Jie is a second-year master's student in Shanghai Jiao Tong University School of Medicine, and Lu Jianfei is a post-doctoral student in Shanghai Jiao Tong University School of Medicine.
Introduction to reviewers
is a special-appointed professor at the University of Texas at Houston Medical College of Shanghai Jiaotong University. Professor of the Academy.
”
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