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Editor | xi Every activity in our daily life, such as walking, eating, drinking, breathing, and even sitting still, is inseparable from muscle contraction.
Muscle control is inseparable from a structure in the human body called neuromuscular junction, which is a link between motor neurons and skeletal muscle fibers (called synapses in neuroscience).
The neuromuscular junction is a chemical synapse.
The motor neuron membrane slightly releases acetylcholine, which activates the acetylcholine receptors on the muscle cell membrane to produce potential changes, so that the brain's instructions are transmitted to the muscle fibers, thereby causing them to contract.
The neuromuscular junction is very efficient.
Although it occupies less than one thousandth of the surface of the muscle, it can transmit signals efficiently and accurately.
One of the keys is the high concentration of acetylcholine receptors on the muscle fiber membrane.
Many myasthenia diseases such as congenital myasthenia, myasthenia gravis, and amyotrophic lateral sclerosis (gradual freezing) have neuromuscular junction structure and function disorders.
Neuromuscular junction formation is an interesting process.
The muscle fibers have spontaneously formed some slender acetylcholine receptor aggregates before the motor nerve endings arrive; after the motor nerve endings arrive, the receptor aggregates on the surface of the muscle fibers that contact the nerve endings become larger or form new aggregates.
At the same time, the acetylcholine receptor aggregates that were not innervated outside the joint gradually disappeared.
It is estimated that the concentration of acetylcholine receptors in the membrane behind the joint is about 10,000 – 20,000/μm2, while the concentration of extrasynaptic receptors is only 10/μm2.
If the muscle fibers are compared to a row of ten-section high-speed trains, each car has 100 rows of seats, and the acetylcholine receptors are only gathered on the ceiling of the size of a row of seats in the middle car.
Imagine that one end of the receptor is outside the compartment, like a high-speed rail "braid" (pantograph), which binds to the neurotransmitter acetylcholine, and the other end is inside the compartment and interacts with many other proteins.
These protein molecules are like many hydrogen balloons.
Hanging below the acetylcholine receptor, it participates in the accumulation of receptors and the formation of neuromuscular junctions.
One of the key proteins is Rapsn, which is only 43 kD.
It can bind to both acetylcholine receptors and cytoskeleton regulatory proteins.
Therefore, the traditional view is that the role of Rapsn is to anchor the receptor to the skeleton molecule.
Recent studies have found that in addition to binding receptors and cytoskeleton regulatory proteins, Rapsn also binds to many other postsynaptic proteins; in addition, it also has the catalytic function of enzymes, stabilizing acetylcholine receptors through ubiquitination (neddylation).
The mechanism by which muscle fibers spontaneously form acetylcholine receptor aggregates is not clear, but the nerve-induced aggregates are caused by agrin.
Aggregin is released from the nerve endings and binds to the muscle fiber membrane protein Lrp4 protein to activate the tyrosine kinase Musk, which is also located on the muscle cell membrane, leading to receptor aggregation.
Aggregin, Lrp4, Musk or Rapsn mutant mice cannot form acetylcholine receptor aggregates and neuromuscular junctions; their genetic mutations can cause congenital myasthenia, while patients with myasthenia gravis have anti-aggregin, Lrp4 or/ And Musk's antibodies, all of which indicate that these protein molecules play a very important role in the formation and function of neuromuscular junctions.
Despite this, little is known about the signaling mechanism downstream of Musk.
On May 24, 2021, Dr.
Guanglin Xing of Case Western Reserve University and others published a research article entitled Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation in Neuron, revealing the new mechanism of Rapsn. They found that Rapsn is capable of liquid-liquid phase separation, which spontaneously forms condensates without membranes.
They demonstrated that these aggregates play an important role in the aggregation of post-synaptic acetylcholine receptors and the formation of neuromuscular junctions.
The so-called liquid-liquid phase separation refers to the phase transformation of proteins or other components into aggregates with liquid characteristics in a liquid solution.
The author found that the purified Rapsn can be transformed into bead-like aggregates in physiological solutions.
These aggregates exhibit liquid characteristics, and two Rapsn aggregates can fuse into a larger aggregate after contact; if part of the aggregate is quenched by fluorescence, the signal will recover quickly, indicating that the Rapsn in the aggregate and the Rapsn in the surrounding solution Can be exchanged freely.
Not only that, Rapsn can form liquid-like aggregates in mammalian cells, cultured myotubes, and muscle fibers of mice.
Significantly, Rapsn can recruit acetylcholine receptors, cytoskeleton regulatory proteins and signaling proteins into its aggregates.
These results suggest that the aggregates formed by Rapsn liquid-liquid phase separation have two functions.
First, the Rapsn aggregates provide a platform for the aggregation of acetylcholine receptors and cytoskeleton proteins, and mediate the binding of receptors to the cytoskeleton; second, Rapsn aggregates have a carrier function.
They recruit molecules that regulate receptor aggregation by exchanging with surrounding solutions and fusion with aggregates, just like carts moving those balloons to the receptors gathering position to promote the formation of neuromuscular junctions.
These findings provide a mechanism for how muscle fibers form aggregates of acetylcholine receptors before the arrival of nerve endings.
Compared with agglutinin, Lrp4, and Musk, Rapsn is more conserved in species evolution; for example, nematodes only have Rapsn, but no agglutinin, Lrp4 and Musk genes, suggesting that Rapsn aggregates are the basis for receptor aggregation and synapse formation.
The authors also found that the Aggregin-Lrp4-Musk signaling pathway promotes the liquid phase separation of Rapsn, suggesting a new mechanism of action downstream.
15% of patients with congenital muscle strength are caused by Rapsn mutation, and there are about 60 mutation sites.
The author studied the effects of these mutations on the formation of aggregates and its carrier function, and found that some mutations (L14P, N88K, R164H) inhibit Rapsn liquid-liquid phase separation, and other mutations (L326P, E147K, 1177del2) may affect the formation of aggregates.
It has no effect, but inhibits the carrier function of Rapsn and prevents Rapsn from recruiting acetylcholine receptors or other postsynaptic proteins.
The accumulation of acetylcholine receptors in muscle fibers of N88K and R164H mutations is blocked, and the formation of neuromuscular junctions in mutant mice is severely defective.
These results provide genetic evidence for the physiological role of Rapsn liquid-liquid separation.
This study suggests that Rapsn liquid-liquid separation may be a new mechanism of post-synaptic acetylcholine receptor aggregation and neuromuscular junction formation.
Dr.
Xing Guanglin from Case Western Reserve University is the first author of the paper, and Professor Mei Lin and Professor Xiong Wencheng are the co-corresponding authors of the paper.
Original link: Plate maker: Instructions for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article, and personal forwarding and sharing are welcome.
Reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated.
Muscle control is inseparable from a structure in the human body called neuromuscular junction, which is a link between motor neurons and skeletal muscle fibers (called synapses in neuroscience).
The neuromuscular junction is a chemical synapse.
The motor neuron membrane slightly releases acetylcholine, which activates the acetylcholine receptors on the muscle cell membrane to produce potential changes, so that the brain's instructions are transmitted to the muscle fibers, thereby causing them to contract.
The neuromuscular junction is very efficient.
Although it occupies less than one thousandth of the surface of the muscle, it can transmit signals efficiently and accurately.
One of the keys is the high concentration of acetylcholine receptors on the muscle fiber membrane.
Many myasthenia diseases such as congenital myasthenia, myasthenia gravis, and amyotrophic lateral sclerosis (gradual freezing) have neuromuscular junction structure and function disorders.
Neuromuscular junction formation is an interesting process.
The muscle fibers have spontaneously formed some slender acetylcholine receptor aggregates before the motor nerve endings arrive; after the motor nerve endings arrive, the receptor aggregates on the surface of the muscle fibers that contact the nerve endings become larger or form new aggregates.
At the same time, the acetylcholine receptor aggregates that were not innervated outside the joint gradually disappeared.
It is estimated that the concentration of acetylcholine receptors in the membrane behind the joint is about 10,000 – 20,000/μm2, while the concentration of extrasynaptic receptors is only 10/μm2.
If the muscle fibers are compared to a row of ten-section high-speed trains, each car has 100 rows of seats, and the acetylcholine receptors are only gathered on the ceiling of the size of a row of seats in the middle car.
Imagine that one end of the receptor is outside the compartment, like a high-speed rail "braid" (pantograph), which binds to the neurotransmitter acetylcholine, and the other end is inside the compartment and interacts with many other proteins.
These protein molecules are like many hydrogen balloons.
Hanging below the acetylcholine receptor, it participates in the accumulation of receptors and the formation of neuromuscular junctions.
One of the key proteins is Rapsn, which is only 43 kD.
It can bind to both acetylcholine receptors and cytoskeleton regulatory proteins.
Therefore, the traditional view is that the role of Rapsn is to anchor the receptor to the skeleton molecule.
Recent studies have found that in addition to binding receptors and cytoskeleton regulatory proteins, Rapsn also binds to many other postsynaptic proteins; in addition, it also has the catalytic function of enzymes, stabilizing acetylcholine receptors through ubiquitination (neddylation).
The mechanism by which muscle fibers spontaneously form acetylcholine receptor aggregates is not clear, but the nerve-induced aggregates are caused by agrin.
Aggregin is released from the nerve endings and binds to the muscle fiber membrane protein Lrp4 protein to activate the tyrosine kinase Musk, which is also located on the muscle cell membrane, leading to receptor aggregation.
Aggregin, Lrp4, Musk or Rapsn mutant mice cannot form acetylcholine receptor aggregates and neuromuscular junctions; their genetic mutations can cause congenital myasthenia, while patients with myasthenia gravis have anti-aggregin, Lrp4 or/ And Musk's antibodies, all of which indicate that these protein molecules play a very important role in the formation and function of neuromuscular junctions.
Despite this, little is known about the signaling mechanism downstream of Musk.
On May 24, 2021, Dr.
Guanglin Xing of Case Western Reserve University and others published a research article entitled Membraneless condensates by Rapsn phase separation as a platform for neuromuscular junction formation in Neuron, revealing the new mechanism of Rapsn. They found that Rapsn is capable of liquid-liquid phase separation, which spontaneously forms condensates without membranes.
They demonstrated that these aggregates play an important role in the aggregation of post-synaptic acetylcholine receptors and the formation of neuromuscular junctions.
The so-called liquid-liquid phase separation refers to the phase transformation of proteins or other components into aggregates with liquid characteristics in a liquid solution.
The author found that the purified Rapsn can be transformed into bead-like aggregates in physiological solutions.
These aggregates exhibit liquid characteristics, and two Rapsn aggregates can fuse into a larger aggregate after contact; if part of the aggregate is quenched by fluorescence, the signal will recover quickly, indicating that the Rapsn in the aggregate and the Rapsn in the surrounding solution Can be exchanged freely.
Not only that, Rapsn can form liquid-like aggregates in mammalian cells, cultured myotubes, and muscle fibers of mice.
Significantly, Rapsn can recruit acetylcholine receptors, cytoskeleton regulatory proteins and signaling proteins into its aggregates.
These results suggest that the aggregates formed by Rapsn liquid-liquid phase separation have two functions.
First, the Rapsn aggregates provide a platform for the aggregation of acetylcholine receptors and cytoskeleton proteins, and mediate the binding of receptors to the cytoskeleton; second, Rapsn aggregates have a carrier function.
They recruit molecules that regulate receptor aggregation by exchanging with surrounding solutions and fusion with aggregates, just like carts moving those balloons to the receptors gathering position to promote the formation of neuromuscular junctions.
These findings provide a mechanism for how muscle fibers form aggregates of acetylcholine receptors before the arrival of nerve endings.
Compared with agglutinin, Lrp4, and Musk, Rapsn is more conserved in species evolution; for example, nematodes only have Rapsn, but no agglutinin, Lrp4 and Musk genes, suggesting that Rapsn aggregates are the basis for receptor aggregation and synapse formation.
The authors also found that the Aggregin-Lrp4-Musk signaling pathway promotes the liquid phase separation of Rapsn, suggesting a new mechanism of action downstream.
15% of patients with congenital muscle strength are caused by Rapsn mutation, and there are about 60 mutation sites.
The author studied the effects of these mutations on the formation of aggregates and its carrier function, and found that some mutations (L14P, N88K, R164H) inhibit Rapsn liquid-liquid phase separation, and other mutations (L326P, E147K, 1177del2) may affect the formation of aggregates.
It has no effect, but inhibits the carrier function of Rapsn and prevents Rapsn from recruiting acetylcholine receptors or other postsynaptic proteins.
The accumulation of acetylcholine receptors in muscle fibers of N88K and R164H mutations is blocked, and the formation of neuromuscular junctions in mutant mice is severely defective.
These results provide genetic evidence for the physiological role of Rapsn liquid-liquid separation.
This study suggests that Rapsn liquid-liquid separation may be a new mechanism of post-synaptic acetylcholine receptor aggregation and neuromuscular junction formation.
Dr.
Xing Guanglin from Case Western Reserve University is the first author of the paper, and Professor Mei Lin and Professor Xiong Wencheng are the co-corresponding authors of the paper.
Original link: Plate maker: Instructions for reprinting on the eleventh [Non-original article] The copyright of this article belongs to the author of the article, and personal forwarding and sharing are welcome.
Reprinting is prohibited without permission, the author has all legal rights, and offenders must be investigated.
