Since October 4, 2021, Nobel Prize in Physiology or Medicine will be announced on the first day of the Nobel Prize in Physiology or Medicine. Published many articles about the interpretation of the 2021 Nobel Prize in Physiology or Medicine. These include:
V. Arden 帕塔普蒂安The discovery of ion channels with mechanical force-sensing receptors
(1) The discovery of TRPV1 is a major breakthrough
We have introduced in the previous issue of Physiology or Nobel in 2021 Award winner Professor David Julius (David Julius) One of the main achievements is the use of capsaicin from peppers to identify "temperature-sensing receptors",The capsaicin receptor, TRPV1, one of the temperature-sensitive receptors was discovered.
When Professor Julius studied the ability of this protein to respond to heat, he discovered that this receptor is an ion channel that is activated at temperatures that feel pain.
Transient receptor potential channel TRP (Transient receptor potential) is a type of cell channel protein. First, it was discovered in Drosophila photoreceptor cells that carrying trp mutations prevents the cells from responding to continuous light stimulation, but can only generate transient potentials.
TRP is expressed in multiple tissues. According to different cell types, the channel opens to allow cations such as calcium ions to flow into the cells and change the state of the cells that are affected by different stimuli.
2021 Nobel Laureate in Physiology or Medicine Professor David Julius
strong22 The strong TRP family can be divided into the following sub-families: strong _strong50 (strong
) canonical),
TRPM (melastatin),
TRPV (vanilloid),
TRPA (ankyrin),
strong
strong
coli TRPP (strongstrong 22)
strong 22 strong TRPA (ankyrin) (ankyrin), _strong50 strong
Most TRP channels are located in the plasma membrane of the cell, and some channel proteins can be located on the endosomes and lysosome membranes of organelles to function, such as TRPML subfamily proteins.
TRPV1 refers to "transient receptor potential cation channel, subfamily V, member 1" (transient receptor potential cation channel, subfamily V, member 1), which is a protein in human genes Encoded by the TRPV1 gene. This channel belongs to an ion channel, a member of the transient receptor potential family, and belongs to the TRPV group (ie, transient receptor potential channel, subclass V).
TRPV1 is a ligand-gated non-selective cation channel that can be stimulated by various extrinsic and intrinsic physical and chemical stimuli, such as: temperature over 43℃, low pH (acidic environment), endogenous The cannabinoids arachidonic acid ethanolamine, N-arachidonic dopamine and capsaicin. This channel was found to exist in the central nervous system and peripheral nerve systems, and it is involved in the transmission and modulation of pain , as well as the integration of various pain information.
Coincidentally, through the same experimental process, Julius’ research team also found another receptor that can be activated by cold—TRPM8.
TRPM8, transient receptor cation potential channel, subclass M, member 8 (TRPM8), is a protein that exists in humans and is encoded by the TRPM8 gene, which is also called cold and menthol receptor 1 (CMR1)
Coincidentally, not only ambient temperature can activate this receptor, but menthol can also activate this receptor. This also leads to an inexplicable refreshing feeling when we use peppermint toothpaste or eat peppermint hard candy.
It can be said that the discovery of other temperature sensing receptors is a major breakthrough in TRPV1. For example, the two Nobel Prize winners, Julius and Pataptian, independently used the chemical menthol (menthol) to identify TRPM8, a receptor that has been shown to be activated by cold. In addition, some other ion channels related to TRPV1 and TRPM8 have also been discovered, and these ion channels can be activated by a series of different temperatures.
(2) Discovery of mechanical force-sensing receptors
Although the mechanism of sensing temperature is gradually clarified under the exploration of scientists, how mechanical stimuli and pressure are transformed into tactile stimuli The mystery is still a mystery.
Researchers have previously discovered mechanical force-sensing receptors in bacteria, but the tactile mechanism of vertebrates is still unknown. Pataptian, who works at the Scripps Research Center in La Jolla, California, hopes to find this elusive mechanical force to stimulate the sensory receptor.
Pataptian and his collaborators first identified a cell line, which emits a measurable electrical signal when a single cell is pricked by a micropipette. They speculated that the receptor activated by mechanical force is an ion channel, and then they identified 72 candidate genes encoding possible receptors. Then activate them one by one,Used to find genes that are truly related to mechanosensing.
After painstaking exploration, Pataptian and his colleagues successfully identified a single gene whose silencing made the cells insensitive to the prick of the micropipette. As a result, a new and completely unknown mechanically sensitive ion channel was discovered and named "PIEZO1". This name is taken from the pressure (í; píesi) in the Greek word .
was compared with PIEZO1, and the second related gene was also found, which was named "PIEZO2".
(3) Exploring the highlight moment in the process of tactile mechanism
pIEZO2p pIEZO2p The highlight moment in the middle.PIEZO is an ion channel, that is, a channel on the cell membrane that allows ions to pass through, and this ion channel is just sensitive to cell tension. In addition, they found that sensory neurons can express high levels of PIEZO2. Further studies have determined that PIEZO1 and PIEZO2 are ion channels that can be activated by the pressure on the cell membrane surface.
Pataputian’s breakthroughs led him and other teams to publish a series of papers, proving that the PIEZO2 ion channel is essential to touch.
In addition, PIEZO2 has been shown to play a key role in extremely important perceptions such as body posture and movement (called proprioception).
PIEZO channel is responsible for sensing mechanical force.For each of our hugs, we use every tool, including our mobile phones every day. Maybe everyone is accustomed to the occurrence of these behaviors, but these actions depend on the feeling of force. It is actually made by PIEZO. mediate.
In further research, PIEZO1 and PIEZO2 channels have been shown to regulate other important physiological processes, including blood pressure, breathing and bladder control. The loss of
PIEZO1 gene function can lead to a lymphatic malformation , which manifests as lymphedema of the face and limbs, indicating that PIEZO1 is involved in the development of the corresponding lymphatic structure. Gain-of-function mutations in PIEZO1 can cause hemolytic anemia , macrocytosis, lip-shaped red blood cells, and red blood cell dehydration.
PIEZO2 gene mutation is also the basis of several genetic diseases, which are manifested by changes in touch, vibration and proprioception. Among them, the proprioception, touch and vibration of patients with PIEZO2 deficiency syndrome are significantly weakened, which can lead to sensory ataxia, difficulty in distinguishing distance, abnormal gait, muscle weakness and atrophy, scoliosis, perinatal respiratory distress and Bladder-derived dysuria, etc. Gain-of-function mutations of PIEZO2 are manifested as abnormal eye movements, short stature, cleft palate, and micrognathia.
First of all, the temperature sensation and the mechanical force sensation including touch and proprioception add up exactly to be somatosensation; secondly, temperature and mechanical force are both physical stimuli (olfactory taste They are all chemically stimulated sensations); again, temperature and mechanical force receptors are all ion channels (visual receptors, olfactory receptors, and taste receptors except salty and sour taste receptors are all G protein-coupled receptors).
In terms of the greatest scientific contribution,Julius’ laboratory discovered TRPV1, the first (thermal) temperature-sensing receptor in mammals, and Pataptian’s laboratory discovered the first type of mechanical force-sensing receptors PIEZO1 and PIEZO2 in mammals. But the two laboratories independently discovered the receptor TRPM8 that senses low temperature, and Pataputian's laboratory also discovered the receptor TRPA1 that senses nociceptive low temperature stimulation.
The reason given by the Nobel Prize Committee is: "Discover temperature and tactile receptors", and focused on TRPV1 (heat receptor), TRPM8 (cold receptor) and PIEZO (force receptor) ) Discovery of three types of ion channels.
In the past decade, research on PIEZO and other mechanically sensitive ion channels has flourished. In the past three years, more than 300 papers have been published around PIEZO alone. One of the issues that everyone is most concerned about is how the proteins located on the cell membrane perceive and respond to it. Using the cryo-electron microscope (cryo-EM), scientists have made progress in revealing the unique three-leaf structure of PIEZO.
Fortunately, in 2013, when Xiao Bailong, a neuroscientist at Tsinghua University , set up his own laboratory, another technique for obtaining high-resolution structural images appeared: cryo-electron microscopy. His research team used this technology to report the structure of PIEZO1 for the first time in 2015. Xiao Bailong had previously engaged in postdoctoral research in Pataputian's laboratory. In September 2020, Xiao Bailong's team further obtained the structure diagram of PIEZO2, which is similar in size and shape to PIEZO1.
The PIEZO2 image of Xiao Bailong’s team is the clearest structural picture taken from the angle of the tail of the three blades so far. These three blades are constantly moving, so it is difficult to capture a clear picture. image. The resulting image is very stunning.The three PIEZO proteins form trimers across the cell membrane. With the central hole as the center, the three proteins hover outward, like a propeller blade. They bend upwards and outwards, forming a deep depression on the surface of the cell.
In addition to structural studies, from a functional point of view, researchers have discovered that PIEZO protein has more than one effect in the body.
PIEZO1-mediated mechanical transduction is involved in the regulation of red blood cell volume, bone development and remodeling, cardiovascular development and function, kidney function, axon regeneration, innate immunity, fat inflammation and adipogenesis, stress pancreatitis, intestinal peristalsis And colitis and other physiological and pathological processes.
and PIEZO has a broader function, almost involved in the perception of mechanical forces in various tissues, organs and physiological processes in the body, including sensory neurons, endothelial cells, red blood cells, smooth muscle cells, epithelial cells, and A variety of cell types such as osteoblast mediate mechanically sensitive cation currents.
PIEZO2 is a mechanical force sensing receptor on primary sensory neurons and receptor cells (such as Merkel cells), which mediates light touch, touch pain, proprioception, airway extension and lung expansion, and blood pressure reflex arc Regulation (together with PIEZO1), low-threshold bladder extension and urinary tract urination and other physiological and pathological functions.
From another perspective, it has an important correlation with many diseases. Some gene mutations in the PIEZO channel can cause a variety of human genetic diseases. The PIEZO channel normally has relatively important physiological functions, and abnormalities can cause many The human genetic disease shows that it plays an indispensable role in the function of the human body.
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