Cartography | Wang Ruonan
Winner of the 2021 Nobel Prize in Physiology or Medicine
David Julius, a professor at the University of California, San Francisco
Image source: physiology.ucsf.edu
Scripps Institute Professor Ardem Patapoutian
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Just now, the Karolin Medical School in Sweden announced that the 2021 Nobel Prize in Physiology or Medicine will be awarded to David Julius, a professor at the University of California, San Francisco (UCSF) and Ardem Patapoutian of the Scripps Institute, for their discovery of perceptual temperature and tactile receptors.
In 2020, The Intellectual reported that two scientists had won the Covelli Prize and reissued it today. A special article from The Intellectual, which combs through the process by which David Julius discovered the Trp ion channel and the current state of research in the field.
Written by | Xin Ling
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The secret of nerve perception of temperature and pressure
David Julius of the University of California, San Francisco, and Adem Pataptian of the Scripps Institute have discovered in their separate studies the molecular mechanisms by which the human body perceives temperature, pressure, and pain, providing an important basis for the study of physical diseases related to touch.
Molecular receptors that perceive external stimuli are the biological basis of the five major sensory systems of human beings. Although we have long discovered molecular receptors related to vision and smell, it has always been a mystery for the sense of touch,— including the human body's perception of temperature (cold and warm), mechanical forces (such as shaking hands), and harmful substances (such as pain from eating chili peppers).
Biologist Rao Yi once wrote an article (see Rao Yi: records of domestic doctors) that in the 1980s, Julius began to use the relatively new method of expressing clones to find serotonin receptors, more than a decade later, he continued to use this method to find receptors for capsaicin (a compound in peppers that can cause burning sensations), and in 1997 found a capsaicin-activated protein molecule VR1, and found that VR1 can be activated by heating, because capsaicin is known to be related to pain pathways, So this work also uncovers part of the mechanism of temperature sensation and the peripheral sensation of pain. In the 1997 article, Julius also confirmed that VR1 belongs to the family of TRP channels, and that the TRP gene was first discovered in fruit flies as early as 1969, but its function has not been known. Thus, Rao commented that while Julius was not the first scientist to discover the TRP gene, he found that the proteins encoded by the TRP gene play an important role in the sensory system (temperature, pressure, etc.). "Putting him (Julius) and Ardem together is because they both contribute to the feeling of stress. Among them, for long-pending hearing, they and others contribute directly or indirectly. Rao Yi said.
Xiao Bailong, a researcher at Tsinghua University's School of Pharmacy, told Intellectuals that Julius' team later discovered other receptors in the family, such as the cool receptor and the mustard oil receptor. This newly discovered TRPV1 and related channels are now a focus for the development of new analgesics.
"David Julius's work is very systematic, from discovering receptors that feel pain in the peripheral areas all the way to its structural and functional relationships, including physiologically studying other receptors through gene knockout techniques, this is a series of work, David Julius award I think is well deserved." Li Yulong, a researcher at Peking University's School of Life Sciences, commented.
Patapultian and Julius were studying the problem of tactile receptors almost simultaneously. After discovering cool (menthol), mustard oil, and warm receptors, Pataputian decided to take a hit on the more challenging search for mechanical force receptors. The study of mechanical force is extremely difficult, one is to find a suitable stimulus method, and the other is to record the generated current.
Bertrand Coste, a postdoctoral fellow in Pataputian's group, looked for cells in a glioma cell line that could be grown in a laboratory dish and responded to changes in pressure from light touch by generating electrical signals. More than 300 candidate genes with high expression in that type of cell were then carefully selected from more than 20,000 coding genes in humans, and then cells that were missing (knocked down) these genes one by one were cultured. The samples were then tested one by one to look for genes that, when missing, caused the cells to lose their induced current. After more than three years of unremitting efforts, the 72 candidate gene on the list was finally determined to have this function. They named the gene PIEZO, which means pressure in Greek. PIEZO is present in both animals and plants and is highly conserved in evolution, suggesting that it is very important in function.
Dr. Bailong Xiao, who was also engaged in postdoctoral research in the Partaputian research group, witnessed this exciting discovery process and proved in subsequent studies that PIEZO protein forms a new class of pressure-sensitive ion channels. Xiao Bailong pointed out: "The process of finding stress receptors is full of risks, the candidate gene list may be incomplete, and the knockout process may also have technical problems, but the persistent efforts have finally achieved this milestone scientific discovery."
Patapultian quickly identified PITEZOs as essential genes for pressure sensing in mammals. His research shows that PIEZOs form ion channels that are directly responsible for the pressure sensing of Merkel cells and haptic terminals within the skin, as well as proprioceptors (receptors where sensory nerve endings sit within muscles that sense and respond to the body's position, posture, and movement in space).
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 opens the door to mechanobiology, an emerging field of science at the intersection of biology, engineering, and physics that focuses on how changes in the physical and mechanical properties of cells and tissues affect health and disease.
"Ardem is an extremely intelligent scientist with a forward-looking vision, but he is never satisfied with his existing achievements, constantly exploring, full of desire to innovate. He has a lot of trust in the researchers in his research group and always fully supports them in exploring cutting-edge scientific problems. He deserves the Covilly Prize for his discovery and research on the PIEZO Channel. Xiao Bailong said.
"The two winners have made systematic and landmark contributions to the study of the molecular mechanisms of peripheral perception, and this award is well deserved." Li Yulong said. He believes that their award once again shows that excellence in basic science requires time accumulation and curiosity, which is exactly what Chinese scientists are actively striving for.
Note: The above article is excerpted from the 2020 Intellectuals article: 7 scientists won the Corvelli Prize, but the award ceremony is not until 2022.
Attached: Past and present lives of the TRP channel
Written by | Qi Xin, Li Jie, Lu Jianfei
Audit | Xu Tianle Zhu Xi Li Haitao
Responsible editor| Chen Xiaoxue
Cell signal transduction relies on multiple receptor proteins on the cell membrane. Among them, ion channels play a key role in the immediate perception of intracellular and internal and external signals and the regulation of adaptive changes. In 2003, Peter Agre and Roderick Mackinnon were jointly awarded the Nobel Prize in Chemistry for discovering water channels and explaining the principles of ion selectivity of voltage-gated potassium channels.
The Transient receptor potential (TRP) channel we introduce today has also attracted generations of scientists to explore it with its complex regulatory mechanisms and rich physiological functions.
1
A bonus
Compared with our study of voltage-gated ion channels, the study of TRP channels started late.
In 1969, D. J. Cosens and Aubrey Manning of the Department of Zoology at the University of Edinburgh in the United Kingdom used Ethylmethane sulfonate (EMS) as a mutagen on Drosophila nigricane to screen a mutant by artificial mutagenesis, which had abnormal phototropism and retinal potential, and sustained photostimulation only caused a transient negative potential of the retina, rather than the usual continuous, platform-like changes. And does not produce an effective response when the second light stimulation comes [1].
Craig Montell, a postdoc in gerald Rubin's lab at the University of California, Berkeley, subsequently found that this was due to a mutation in an ionic channel membrane protein in Drosophila melabens, so they pioneered the cloning of the gene and named the protein Transient Receptor Potential (TRP) Channel [2]. Wild-type TRP channels mediate a continuous platform current of light activation in insect vision cells. The same channel does not exist in vertebrates, but there are many channel proteins that are evolutionarily associated with the initial TRP channels of Drosophila, forming a protein superfamily.
Drosophila-based TRP was the first to be discovered, and all superfamily members are also named after TRP and belong to seven subfamilies of TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin), TRPA (Ankyrin), TRPP (Polycystin), TRPML (Mucolipin), and TRPN (NOMP-C) based on differences in protein sequences (Figure 1). TRPN is found only in invertebrates, and the initial Drosophila TRP belongs to the TRPC subfamily.
Figure 1 TRP channel subfamily[3]
The mammalian TRP channel is not involved in visual perception, but is widely involved in the production and regulation of pain sensation, with TRPV1 as the main representative. It has long been known that cayenne pepper leaching fluid selectively activates nociceptive neurons in the Dorsal root ganglion (DRG), inducing them to produce action potentials [4] and transmitting injury stimuli to the central nervous system to produce pain sensations. But by what mechanism does the stimulating molecule capsaicin activate neurons?
In order to screen the receptors that bind to capsaicin, in 1997, a team led by Professor David Julius of the University of California, San Francisco, extracted more than 16,000 mRNAs from rat DRG, divided them into different components, and transferred them into tool cells to detect their response to capsaicin, and successfully cloned the capsaicin receptor VR1. Analysis of the VR1 protein sequence suggests that VR1 belongs to the TRP protein superfamily and is therefore named the TRPV1 channel [5].
The gene encodes a 6-fold transmembrane protein, and the channel exhibits a high degree of calcium ion permeability. TRPV1 can be specifically activated by capsaicin, but also by high temperatures above 42 ° C, thus not only determining the principle of capsaicin activating sensory neurons, but also linking pain and temperature sensation for the first time, revealing the molecular mechanism of why people eat chili peppers at the same time feel spicy and hot.
To date, more than 50 TRP channels have been found from yeast, insects, fish and mammals. Although they belong to the same TRP superfamily, their sequence consistency does not exceed 20%, and there are also huge differences in channel characteristics, some TRP channels are expressed on the plasma membrane, integrating intracellular and extracellular information, mediating non-selective cation inflow, and some are distributed on the organelle membrane, regulating the release of intracellular Ca2+ [6]. To understand the mechanisms and physiological functions of channel opening, it is imperative to analyze their fine structure.
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Cryo-EM key technology revolution triggers a breakthrough in structural analysis
One of the most homologous mammalian TRP channels with the Drosophila Trp gene and the earliest full-length resolved TRP channel is TRPC3. TRPC3 is widely expressed in the nervous system and heart, activated by second messengers such as diacylglycerol (DAG), sensing cytoplasmic calcium depot depletion, open-mediating non-selective cationic currents, participating in multiple physiological processes such as growth cone guidance, synaptic plasticity, vasoconstriction, etc.
In 2007, Chikara Sato et al. collaborated to report the cryo-EM structure of TRPC3, which was the first full-length mammalian TRP channel structure to be resolved [7]. The electron microscope structure shows that TRPC3 consists of four subunits, and the entire channel forms a nested structure, consisting of a spherical cavity in the middle and a discontinuous shell, and when the channel is open, ions enter the cavity through the pores, and flow into the cell through the four openings at the bottom of the cavity. The different domains separated on the housing may also be involved in the fine adjustment of the gating mechanism.
It is followed by the full-length resolution of the TRPV1 channel. In 2013, Professor David Julius collaborated with Professor Cheng Yifan, a Chinese scientist from the same institution as him, and published two articles in Nature magazine in succession, analyzing the structure of the full-length TRPV1 off state and the open state, which was the first membrane protein structure to obtain nearly 3 Å ultra-high resolution by cryo-EM method, which greatly promoted the understanding of the molecular structure of TRP channels and created a new era of using cryo-EM as the main means to study protein structure and protein-to-protein interaction. It also promoted cryo-EM technology to win the 2017 Nobel Prize in Chemistry.
Figure 2 Cheng Yifan, professor at the University of California, San Francisco, | Image source: hhmi.org
Through the analysis of the closed state structure of TRPV1, the researchers found that the channel has a similar structure to the voltage-gated ion channel: TRPV1 is a tetramer, each subunit has six transmembrane α spiral domains, of which the 5th and 6th transmembrane domains together constitute the channel pore region, and the 1st-4th transmembrane domains constitute the voltage receptive site and the capsaicin binding site [8]. The open structure of TRPV1 can be obtained in the presence of resin virulence (capsaicin analogue) and spider toxin DkTx, and by comparing its open and closed state structures, it is found that TRPV1 has a unique two-gate channel activation mechanism (Figure 3) [9], although whether its selective filter constitutes an upper gate that can truly control ion flow is controversial [10]. This work perfectly explains the opening principle and conformational changes of the TRPV1 channel under the activation of two different ligands, capsaicin and proton, but it also raises new questions about whether temperature-mediated TRP channel opening also has a specific structural biological basis.
Fig. 3 TRPV1 two-door channel gating mechanism [9]
3
Spring River Plumbing "TRP" knows
In addition to being activated by ligands, temperature sensitivity is also an important feature of the TRP family. We refer to members of the TRP family, such as TRPV1, which are open at specific temperatures, thermoTRP.
To date, 11 species of ThermoTRP have been identified in mammals, including the thermal receptors TRPV1-TRPV4 and TRPM2-TRPM5, as well as the cold receptors TRPM8, TRPC5 and TRPA1. These ThermoTRPs can feel temperatures across the entire physiological range, from painful burning, to comforting warmth and coolness, to bone-chilling cold.
In addition, ThermoTRP can be activated by chemical ligands, including the capsaicin just mentioned, as well as allicin, cannabinoids, mustard oil, menthol, and cinnamaldehyde (Figure 4).
Fig. 4 ThermoTRP and its chemical ligands
The researchers made full use of a variety of biophysical techniques and methods to explore the mechanism of how temperature activates the ThermoTRP channel. Temperature represents the average kinetic energy of microscopic particles in the region, while heat conduction affects particle arrangement. For peptide chains and proteins, temperature changes will not only affect the polarity of amino acid residues, but also greatly change the conformation of proteins. It is precisely because of this multimodal participation that the process of resolving the ThermoTRP temperature activation mechanism is hindered. At the same time, the differences in temperature sensitivity of different species, for example, the activation temperature threshold of rat rTRPV1 is ~42 °C, while the activation temperature of Vampire bat TRPV1 is about 30 °C, which increases the challenge of identifying the temperature sensing domain.
For TRPV1, the areas identified to participate in temperature gating mainly include the N-terminal, C-terminal, external aperture area, and aperture region (Figure 5).
The N-terminus anchored repeat domain (ARD) determines the heat tolerance of thirteen-striped ground squirrels and bactrian camels, and replacing the rat-derived sqTRPV1 channel with rat-like aspartic acid will mediate increased thermal sensitivity to sqTRPV1 without affecting its capsaicin and acid-induced chemical activation [12]. Experiments have shown that the N-terminus that connects the ARD and the first transmembrane fragment, also known as the membrane proximal domain (MPD), is involved in mediating TRPV1 temperature sensitivity as a temperature receptor and determines the energy change and temperature sensing characteristics during the switching of the TRPV1 channel under temperature stimulation. Using molecular biology to exchange this area into channels such as rTRPV2, hTRPV2, or mTRPV4, not only transforms the temperature-insensitive subtype into a temperature-sensitive channel, but also makes the temperature-sensing characteristics of the wild-type channel the same as that of the TRPV1 channel [13].
In addition, the proximal and distal regions of the C-end of the channel, affected by the endogenous end-cell agonist phosphatidylinositol (Phosphatidylinositol-4, 5-bisphophate, PIP2), are also important modules for sensing temperature stimulation [14,15]. The temperature sensitivity can be exchanged between the thermally activated TRPV1 and the cold-activated TRPM8 C-terminal, especially by introducing the two amino acid residues of TRPV1 Q727 and W752 into the wild-type TRPM8 channel, which directly exhibits thermally activated properties and is not coupled with PIP2 activation, which indicates that temperature sensing differs from the mechanisms that traditional ligand activation relies on [16].
Fig. 5 TRPV1 temperature-sensitive domain [8]
It has been shown that the two intracellular regions of the N-terminal and C-terminal also interact to mediate the thermal inactivation of TRPV1 [17]. In addition to the intracellular region, the channel aperture and the periphery of the channel are also involved in temperature sensitivity regulation, and its key sites, including C617 and C622 located in the channel pore region, and N628, N652, and Y653 located outside the pore region, can significantly affect the temperature sensitivity of TRPV1 after mutation [18,19]. Each species has the most suitable survival temperature, and the evolutionary pressure makes the TRP channel show significant species differences, which also demonstrates the significance of the TRP family for biological adaptation to environmental changes.
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With the spear of the Son, the shield of the Son
Because of its diverse biological functions and flexible open mechanisms, clinical interventions targeting TRP channels have broad application prospects.
Take TRPV1 as an example, which is a very transformative analgesic target [20]. As a receptor that converts injury stimuli into electrical signals, the TRPV1 channel can also cause neuropathic pain when the sensory nerve endings are hyperactivated (Figure 6) [21]. For example, cancer patients sometimes develop severe peripheral neuralgia after chemotherapy, and conventional analgesics cannot be completely relieved. This may be because chemotherapy drugs such as cisplatin, oxaliplatin, and paclitaxel promote the function of TRPV1, causing elevated channel expression levels, channel sensitization, and oxidative stress responses, inducing mechanical, thermal, and cold pain sensitivity reactions [22]. Drugs that target the TRP pathway are effective in relieving the serious adverse effects that cancer patients experience during chemotherapy. For example, resin toxins can act as "molecular scalpels" by specifically activating their receptor TRPV1 channels, causing calcium intracervity and calcium overload in pain-sensing neurons expressing TRPV1, which in turn leads to apoptosis of these neurons as a means of controlling chronic cancer pain [23].
Figure 6 ThermoTRP and pain[11]
At the same time, TRP channels are potential targets for the treatment of respiratory diseases, being widely expressed in immune and structural cells in the lungs and playing a central role in causing respiratory symptoms such as bronchospasm and cough [24]. Inhaling capsaicin activates C fibers and causes a violent cough reflex, which is one of the common features of a range of respiratory diseases such as asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. Targeting subunits such as TRPV1, TRPA1, TRPV4, and TRPM8, which are highly expressed in the respiratory tract, can not only increase lung ventilation and improve airway obstruction, but may also become an adjunctive intervention strategy for reducing pulmonary edema [25], improving respiratory distress, and inhibiting viral transmission between host cells [26] in the treatment of lung infections such as COVID-19[ 26].
In addition, targeting the TRP family, especially the TRPM subfamily, to intervene in neurological diseases also has clinical translational significance. The TRPM2 inhibitor JNJ-28583113 significantly mitigated oxidative stress damage to neurons during ischemic stroke in mice [27], while the TRPM4 subunit not only exacerbated per synaptic NMDAR-mediated neuronal death by promoting membrane transport of N-methyl-D-aspartic acid receptor (NMDAR) [28], Complexes can also be formed with sulfonylurea receptor 1 (SUR1) to increase blood-brain barrier permeability [29], and polymers with aquaporin 4 (Aquaporin 4, AQP4) to exacerbate the swelling of astrocytes during stroke, leading to more severe nerve damage [30]. Exogenous glyburea-targeted SUR1-TRPM4 heteromer intervention ischemic stroke has entered the clinical phase III phase. This further illustrates the application prospects of targeting TRP channels in interventions for central nervous system diseases.
The study of TRP channels continues, which is not only a molecular window for us to understand how the body perceives external stimuli (temperature, pressure, injury stimuli), but also a very inspiring and continuous target exploration epic, and its research paradigm from structure to function has had a profound impact on the study of subsequent membrane proteins. The progress and innovation of clinical medicine are inseparable from the exploration and discovery of basic science, and we hope that with the deepening of our understanding of TRP channels and other membrane proteins, we can truly uncover the mystery of biological evolution and produce more inspiring and clinical translational research results.
Note: Part of the content of this article is excerpted from the public account "Progress of Ion Channel Research"
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About the Author
Qi Xin is a third-year doctoral student at Shanghai Jiao Tong University School of Medicine, Jie Li is a second-year master's student at Shanghai Jiao Tong University School of Medicine, and Jianfei Lu is a postdoctoral fellow at Shanghai Jiao Tong University School of Medicine.
Reviewer Profile
Xu Tianle is a Distinguished Professor at Shanghai Jiao Tong University School of Medicine, Xi Zhu is a Professor at the University of Texas Health Medical Center in Houston, and Haitao Li is a Professor at Tsinghua University School of Medicine.
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