Mechanosensation
Encyclopedia
Mechanosensation is a response mechanism to mechanical stimuli. The physiological foundation for the senses of touch, hearing and balance, and pain is the conversion of mechanical stimuli into neuronal signals: mechanosensation. Mechanoreceptors of the skin, called cutaneous mechanoreceptors, are responsible for touch. Tiny cells in the inner ear, called hair cells, are responsible for hearing and balance. States of neuropathic pain, such as hyperalgesia
and allodynia
, are also directly related to mechanosensation. A wide array of elements are involved in the process of mechanosensation, many of which are still not fully understood.
sheaths, and are either D-hair receptors or nociceptive neurons. Aδ fibers conduct at a rate of up to 25 m/s. D-hair receptors have large receptive fields and very low mechanical thresholds, and have been shown to be the most sensitive of known cutaneous mechanoreceptors. A-fiber mechanoreceptors (AM) also have thin myelination and are known for their "free" nerve endings. It is believed that A-fiber mechanonociceptors have high mechanical sensitivity and large receptive fields, and are responsible for rapid mechanical and heat pain.
sheath at all. C-fibers account for 60-70% of primary afferent neurons that innervate the skin. C-fibers are activated by both mechanical and thermal stimuli, and also respond to algesic chemicals, such as capsaicin
. Some C-fibers respond only to mechanical stimuli. Therefore, classification of C-fibers are broken down further. C-fiber nociceptors which respond to both mechanical and thermal stimuli include C-mechanoheat (C-MH), C-mechanocold (C-MC), and C-mechanoheatcold (C-MHC). C-fiber nociceptors that respond only to mechanical stimuli are called C-mechanonociceptors (C-M). Other groups of C-fibers include C-fiber low threshold mechanoreceptors (C-LT), which are involved in nondiscriminative touch, and mechanically insensitive nociceptors (MIA), which lack mechanosensitivity and are also known as “silent” or “sleeping” nociceptors. C-fibers called C-Mechano insensitive, heat insensitive (C-MiHi) account for about 15-25% of all C-fibers.
at the transduction site. It is believed that rapid, mechanically gated cation channels are characteristic of all sensory neurons. The membrane depolarization, in turn, leads to a sodium-dependent action potential at that location. It is also thought that mechanical strain is detected by ion channels through cytoplasmic and extracellular components. The existence of a distinct transduction process for all sensory neurons is highly unlikely. It has been hypothesized that the attachment of ion channels to cytoplasmic and extracellular structures is responsible for distinguishing mechanical strain on the cell membrane, and that cell curvature may not directly gate these ion channels alone. Mechanosensation also contributes to cell growth and development through extracellular matrix (ECM) interaction and traction of integrin receptors which facilitate adhesion.
(TRP) ion channels introduce the idea that the expression of specific “molecular sensors” govern sensitivity to certain stimuli. Researchers believe that the ability of various somatosensory receptor neurons to respond to specific stimuli is a result of “combinational expression” of various ion channels in each specific neuronal class. Transduction channels work in their specific environment and should be treated as such. TRP channels play a significant role in mechanosensation. There are seven TRP subfamilies: TRPC, TRPM, TRPV, TRPN, TRPA, TRPP, and TRPML. Some of these TRP channels respond to membrane lipid tension, including TRPY and TRPC1. Others respond directly to mechanical force, such as TRPN, TRPA1, and TRPV. Others are activated by a second messenger, such as TRPV4. The TRPA subfamily plays a significant role in thermosensation. For example, TRPA1 is thought to respond to noxious cold and mechanosensation. The cytoplasmic content of each of these differs significantly, leading researchers to doubt that the cytoplasm is the core of mechanosensation.
may be in whole or in part governed by the lipid bilayer
, which contributes to stretch forces which result in opening of the channel. While it is known that the lipid bilayer properties of cell membranes contribute to mechanosensation, it is yet unknown whether the protein interacts with the head groups of the lipids.
and vestibular system
.
which participates in mechanosensation. Each of these bundles are approximately 4-10 μm high and have 30-300 stereocilia
and one kinocilium
, which has motile characteristics. Along the axis of symmetry, each successive row of stereocilia is approximately 0.5-1.0 μm taller, with the kinocilium next to the tallest row. Extracellular structures connect the stereocilia together. These include ankle links (between adjacent stereocilia), shaft links (entire length of hair cell), and cross links (laterally between tips). Tip links run along the tips of the stereocilium, from the shorter end to the longer end. Tip links pull on the ion channels to open them up. It is known that the tip link is made of two different cadherin
molecules, protocadherin 15 and cadherin 23.
of the cell is caused by the inward current which results. This is known as a positive deflection. This process involves the stretching of tip links, which pull the ion channels open. A deflection in the opposite direction is termed negative deflection, and causes tip links to relax and the ion channels to close. Perpendicular deflection is ineffective. It is suspected that the site of transduction channels is at the stereocilia tips. The speed with which ion channels respond to deflection leads researchers to believe that mechanical stimuli act directly upon the ion channel, and do not need a second messenger.
The sensitivity of cilia is primarily due to ciliary length.
The stereocilia of functional hair cells have the ability to convert mechanical deflections to neural signals.
of the tip links. Because the tip links are composed of cadherin molecules, computer modeling using steered molecular dynamics can estimate the stiffness.
s and therefore is a useful technique for studying mechanosensitive ion channels. For example, the blocking of certain subtypes results in a decrease in pain sensitivity, which suggest characteristics of that subtype with regard to mechanosensation.
and medical
disciplines, recent discoveries have noted that primary cilia in many types of cells
within eukaryotes serve as cellular antennae. These cilia play important roles in mechanosensation. The current scientific understanding of primary cilia organelles views them as "sensory cellular antennae that coordinate a large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation."
and allodynia
are examples of neuropathic pain. It is thought that the activation of specialized neuronal nociceptors are responsible for hyperalgesia. Studies suggest that hyperalgesia and allodynia are set off and sustained by certain groups of mechanosensitive sensory neurons. There is a general consensus among the scientific community that neuropeptides and NMDA receptors are crucial to the initiation of sensitization states such as hyperalgesia and allodynia.
is extreme sensitivity to pain. Hyperalgesia to mechanical stimuli extends to a large area around the initial location of the stimulus, while hyperalgesia to thermal stimuli remains in the same location as the initial stimulus. Hyperalgesia which remains in the initial area is known as primary hyperalgesia, and hyperalgesia which extends to a large area is secondary hyperalgesia. Primary hyperalgesia probably relies on a central mechanism. It is argued that MIAs, or C-MiHi primary afferents, are crucial to the initiation of primary hyperalgesia because they have a significant response to capsaicin, which is a chemical commonly used to induce hyperalgesia. Secondary hyperalgesia is believed to be caused by a magnified spinal response to nociceptor stimulation. It is argued that heat sensitive Aδ nociceptors are responsible for secondary hyperalgesia.
is pain resulting from an otherwise nonpainful stimulus. It is believed that restructured synaptic connections in the spinal cord are responsible for allodynia. Pain associated with allodynia can be attributed to myelinated A-fibers as a result of a change in their central functional connectivity. Mechanoreceptors with high sensitivity to movement, namely Aβ fibers, are believed to be responsible. It is not yet known whether just one particular movement sensitive mechanoreceptor or all of them contribute to allodynic pain. There is a general consensus that continuous C-fiber activity at the location of the initial stimulus is responsible for maintaining allodynia.
Hyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
and allodynia
Allodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
, are also directly related to mechanosensation. A wide array of elements are involved in the process of mechanosensation, many of which are still not fully understood.
Cutaneous Mechanoreceptors
Cutaneous mechanoreceptors are physiologically classified with respect to conduction velocity, which is directly related to the diameter and myelination of the axon.Rapidly Adapting and Slowly Adapting Mechanoreceptors
Mechanoreceptors that possess a large diameter and high myelination are called low-threshold mechanoreceptors. Fibers that respond only to skin movement are termed rapidly adapting mechanoreceptors (RA), while those that respond also static indentation are termed slowly adapting mechanoreceptors (SA).Aδ fibers
Aδ fibers are characterized by thin axons and thin myelinMyelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
sheaths, and are either D-hair receptors or nociceptive neurons. Aδ fibers conduct at a rate of up to 25 m/s. D-hair receptors have large receptive fields and very low mechanical thresholds, and have been shown to be the most sensitive of known cutaneous mechanoreceptors. A-fiber mechanoreceptors (AM) also have thin myelination and are known for their "free" nerve endings. It is believed that A-fiber mechanonociceptors have high mechanical sensitivity and large receptive fields, and are responsible for rapid mechanical and heat pain.
C-fibers
C-fibers have slow conduction velocities of less than 1.3 m/s because they do not have a myelinMyelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
sheath at all. C-fibers account for 60-70% of primary afferent neurons that innervate the skin. C-fibers are activated by both mechanical and thermal stimuli, and also respond to algesic chemicals, such as capsaicin
Capsaicin
Capsaicin 2CHCH=CH4CONHCH2C6H3-4--3- ) is the active component of chili peppers, which are plants belonging to the genus Capsicum. It is an irritant for mammals, including humans, and produces a sensation of burning in any tissue with which it comes into contact...
. Some C-fibers respond only to mechanical stimuli. Therefore, classification of C-fibers are broken down further. C-fiber nociceptors which respond to both mechanical and thermal stimuli include C-mechanoheat (C-MH), C-mechanocold (C-MC), and C-mechanoheatcold (C-MHC). C-fiber nociceptors that respond only to mechanical stimuli are called C-mechanonociceptors (C-M). Other groups of C-fibers include C-fiber low threshold mechanoreceptors (C-LT), which are involved in nondiscriminative touch, and mechanically insensitive nociceptors (MIA), which lack mechanosensitivity and are also known as “silent” or “sleeping” nociceptors. C-fibers called C-Mechano insensitive, heat insensitive (C-MiHi) account for about 15-25% of all C-fibers.
Molecular Mechanisms
Known molecular mechanisms of cutaneous mechanosensitivity are not completely understood. Most likely, a single unifying transduction process by which all sensory neurons function does not exist. It is believed, however, that sensory neurons employ fast, mechanically gated cation channels, and that the depolarization that results across the membrane is followed by the generation of a sodium-dependent action potentialAction potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
at the transduction site. It is believed that rapid, mechanically gated cation channels are characteristic of all sensory neurons. The membrane depolarization, in turn, leads to a sodium-dependent action potential at that location. It is also thought that mechanical strain is detected by ion channels through cytoplasmic and extracellular components. The existence of a distinct transduction process for all sensory neurons is highly unlikely. It has been hypothesized that the attachment of ion channels to cytoplasmic and extracellular structures is responsible for distinguishing mechanical strain on the cell membrane, and that cell curvature may not directly gate these ion channels alone. Mechanosensation also contributes to cell growth and development through extracellular matrix (ECM) interaction and traction of integrin receptors which facilitate adhesion.
TRP Channels
The ‘doctrine of specific nervous energies’ states that particular nervous pathway activation causes various sensory modalities. Sensory receptor classification with respect to function suggest that different sensory modalities are governed by separate receptor classes. Transient Receptor PotentialTransient receptor potential
Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous human and animal cell types. There are about 28 TRP channels that share some structural similarity to each other...
(TRP) ion channels introduce the idea that the expression of specific “molecular sensors” govern sensitivity to certain stimuli. Researchers believe that the ability of various somatosensory receptor neurons to respond to specific stimuli is a result of “combinational expression” of various ion channels in each specific neuronal class. Transduction channels work in their specific environment and should be treated as such. TRP channels play a significant role in mechanosensation. There are seven TRP subfamilies: TRPC, TRPM, TRPV, TRPN, TRPA, TRPP, and TRPML. Some of these TRP channels respond to membrane lipid tension, including TRPY and TRPC1. Others respond directly to mechanical force, such as TRPN, TRPA1, and TRPV. Others are activated by a second messenger, such as TRPV4. The TRPA subfamily plays a significant role in thermosensation. For example, TRPA1 is thought to respond to noxious cold and mechanosensation. The cytoplasmic content of each of these differs significantly, leading researchers to doubt that the cytoplasm is the core of mechanosensation.
Lipid Bilayer
There is evidence that mechanosensitive channelsMechanosensitive channels
Mechanosensitive channels or mechanosensitive ion channelsare membrane proteins capable of responding over a wide dynamic range to external mechanical stimuli. They are found in prokaryotes and eukaryotes...
may be in whole or in part governed by the lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
, which contributes to stretch forces which result in opening of the channel. While it is known that the lipid bilayer properties of cell membranes contribute to mechanosensation, it is yet unknown whether the protein interacts with the head groups of the lipids.
Hair Cells
Hair cells are the source of the most detailed understanding of mechanosensation. They are present in sensory epithelia of the inner ear and are responsible for the auditory systemAuditory system
The auditory system is the sensory system for the sense of hearing.- Outer ear :The folds of cartilage surrounding the ear canal are called the pinna...
and vestibular system
Vestibular system
The vestibular system, which contributes to balance in most mammals and to the sense of spatial orientation, is the sensory system that provides the leading contribution about movement and sense of balance. Together with the cochlea, a part of the auditory system, it constitutes the labyrinth of...
.
Structure
The bundle of cilia that projects from the surface of the hair cell is the organelleOrganelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
which participates in mechanosensation. Each of these bundles are approximately 4-10 μm high and have 30-300 stereocilia
Stereocilia
In the inner ear, stereocilia are the mechanosensing organelles of hair cells, which respond to fluid motion in numerous types of animals for various functions, including hearing and balance. They are about 10–50 micrometers in length and share some similar features of microvilli...
and one kinocilium
Kinocilium
A kinocilium is a special type of cilium on the apex of hair cells located in the sensory epithelium of the vertebrate inner ear.-Anatomy in humans:...
, which has motile characteristics. Along the axis of symmetry, each successive row of stereocilia is approximately 0.5-1.0 μm taller, with the kinocilium next to the tallest row. Extracellular structures connect the stereocilia together. These include ankle links (between adjacent stereocilia), shaft links (entire length of hair cell), and cross links (laterally between tips). Tip links run along the tips of the stereocilium, from the shorter end to the longer end. Tip links pull on the ion channels to open them up. It is known that the tip link is made of two different cadherin
Cadherin
Cadherins are a class of type-1 transmembrane proteins. They play important roles in cell adhesion, ensuring that cells within tissues are bound together. They are dependent on calcium ions to function, hence their name.The cadherin superfamily includes cadherins, protocadherins, desmogleins, and...
molecules, protocadherin 15 and cadherin 23.
Function
When an event occurs which causes the bundle of cilia to deflect toward the taller side, ion channels open, and a depolarizationDepolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
of the cell is caused by the inward current which results. This is known as a positive deflection. This process involves the stretching of tip links, which pull the ion channels open. A deflection in the opposite direction is termed negative deflection, and causes tip links to relax and the ion channels to close. Perpendicular deflection is ineffective. It is suspected that the site of transduction channels is at the stereocilia tips. The speed with which ion channels respond to deflection leads researchers to believe that mechanical stimuli act directly upon the ion channel, and do not need a second messenger.
The sensitivity of cilia is primarily due to ciliary length.
The stereocilia of functional hair cells have the ability to convert mechanical deflections to neural signals.
Current Research
One aspect of hair cell mechanosensation that remains unknown is the stiffnessStiffness
Stiffness is the resistance of an elastic body to deformation by an applied force along a given degree of freedom when a set of loading points and boundary conditions are prescribed on the elastic body.-Calculations:...
of the tip links. Because the tip links are composed of cadherin molecules, computer modeling using steered molecular dynamics can estimate the stiffness.
Computer Simulation
Computer simulation uses molecular dynamics calculations. The tip link consists of two different cadherin molecules. The molecular structure of the general cadherin class is known. The molecular structure is input into the computer, which then calculates how the protein would move using the known forces between atoms. This allows the behavior of the protein to be characterized and stiffness can be calculated. It has been found that the tip links are relatively stiff, so it is thought that there has to be something else in the hair cells that is stretchy which allows the stereocilia to move back and forth.Animal Studies
Animals are often used in research trying to discover the protein. Deaf animals are probably deaf because they have some kind of mutation in this particular protein, so a great deal of research has focused on trying to find animals that are deaf and figure out where the mutation is. For example, there are strains of mice that are deaf. Defects in their hair cells affect not only their hearing but their balance, so they tend to run in circles. These mice have been recognized for several decades as potential for identifying the mutation that caused this deafness and balance problems. Some are mutations in the two cadherins that make up the tip link, and others have been identified but none of them yet are the ion channel.Channel Blocking
FMI-43 is a dye which can be used to block mechanosensitive ion channelMechanosensitive ion channel
Mechanosensitive channels are found in a number of tissues and organisms and are thought to be the sensors for a number of systems including the senses of touch, hearing and balance, as well as participating in cardiovascular regulation and osmotic homeostasis...
s and therefore is a useful technique for studying mechanosensitive ion channels. For example, the blocking of certain subtypes results in a decrease in pain sensitivity, which suggest characteristics of that subtype with regard to mechanosensation.
Future Studies
When the function and mechanisms of hair cells are more fully understood, there are two applications that it could have. These involve both basic research in other fields and clinical applications in the field of hair cells. The mechanism of the hair cell might contribute to the understanding other mechanosensory systems such as the sense of touch. In the field of touch, the ion channel is that is activated is also currently unknown, and it is likely that there are several different ion channels. Eventually, it is hoped that this research can help individuals with hearing impairments. For example, if somebody subjects their ears to extremely loud sounds, then they may experience hearing loss. This is probably a result of the tip links being broken. Normally the tip links grow back in about half a day, but for some people they are more fragile, making those individuals more susceptible to hearing loss. If the cause of this susceptibility could be determined, and if tip link are repair could be understood, then a drug could be developed that would help the tip links grow back more readily. Generally, many people lose hearing in their old age, especially high frequency hearing. This is caused by hair cell death, so it is hoped that that techniques can be developed, such as by using stem cells or other genetic manipulations, to encourage the inner ear to regenerate its hair cells and restore hearing.Cellular antennae
Within the biologicalBiology
Biology is a natural science concerned with the study of life and living organisms, including their structure, function, growth, origin, evolution, distribution, and taxonomy. Biology is a vast subject containing many subdivisions, topics, and disciplines...
and medical
Medicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
disciplines, recent discoveries have noted that primary cilia in many types of cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
within eukaryotes serve as cellular antennae. These cilia play important roles in mechanosensation. The current scientific understanding of primary cilia organelles views them as "sensory cellular antennae that coordinate a large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation."
Neuropathic Pain
HyperalgesiaHyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
and allodynia
Allodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
are examples of neuropathic pain. It is thought that the activation of specialized neuronal nociceptors are responsible for hyperalgesia. Studies suggest that hyperalgesia and allodynia are set off and sustained by certain groups of mechanosensitive sensory neurons. There is a general consensus among the scientific community that neuropeptides and NMDA receptors are crucial to the initiation of sensitization states such as hyperalgesia and allodynia.
Hyperalgesia
HyperalgesiaHyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
is extreme sensitivity to pain. Hyperalgesia to mechanical stimuli extends to a large area around the initial location of the stimulus, while hyperalgesia to thermal stimuli remains in the same location as the initial stimulus. Hyperalgesia which remains in the initial area is known as primary hyperalgesia, and hyperalgesia which extends to a large area is secondary hyperalgesia. Primary hyperalgesia probably relies on a central mechanism. It is argued that MIAs, or C-MiHi primary afferents, are crucial to the initiation of primary hyperalgesia because they have a significant response to capsaicin, which is a chemical commonly used to induce hyperalgesia. Secondary hyperalgesia is believed to be caused by a magnified spinal response to nociceptor stimulation. It is argued that heat sensitive Aδ nociceptors are responsible for secondary hyperalgesia.
Allodynia
AllodyniaAllodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
is pain resulting from an otherwise nonpainful stimulus. It is believed that restructured synaptic connections in the spinal cord are responsible for allodynia. Pain associated with allodynia can be attributed to myelinated A-fibers as a result of a change in their central functional connectivity. Mechanoreceptors with high sensitivity to movement, namely Aβ fibers, are believed to be responsible. It is not yet known whether just one particular movement sensitive mechanoreceptor or all of them contribute to allodynic pain. There is a general consensus that continuous C-fiber activity at the location of the initial stimulus is responsible for maintaining allodynia.
See also
- Aδ fibers
- Action potentialAction potentialIn physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
- Chemical synapseChemical synapseChemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
- Hair cells
- MechanoreceptorMechanoreceptorA mechanoreceptor is a sensory receptor that responds to mechanical pressure or distortion. There are four main types in the glabrous skin of humans: Pacinian corpuscles, Meissner's corpuscles, Merkel's discs, and Ruffini corpuscles...
- NociceptorNociceptorA nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending nerve signals to the spinal cord and brain. This process, called nociception, usually causes the perception of pain.-History:...
- Transient Receptor PotentialTransient receptor potentialTransient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous human and animal cell types. There are about 28 TRP channels that share some structural similarity to each other...