Mechanosensation

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Mechanosensation is the transduction of mechanical stimuli into neural signals. Mechanosensation provides the basis for the senses of light touch, hearing, proprioception, and pain. Mechanoreceptors found in the skin, called cutaneous mechanoreceptors, are responsible for the sense of 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.

Contents

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 to static indentation are termed slowly adapting mechanoreceptors (SA). [1]

Aδ fibers

Aδ fibers are characterized by thin axons and thin myelin 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 myelin 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 afferents (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. [1]

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 potential 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. [1] Mechanosensation also contributes to cell growth and development through extracellular matrix (ECM) interaction and traction of integrin receptors which facilitate adhesion. [2]

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 potential channels (TRP channels) (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. [3] 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. [4] The TRPA subfamily plays a significant role in thermosensation. For example, TRPA1 is thought to respond to noxious cold and mechanosensation. [5] The cytoplasmic content of each of these differs significantly, leading researchers to doubt that the cytoplasm is the core of mechanosensation. [6]

Lipid bilayer

There is evidence that mechanosensitive channels may be in whole or in part governed by the lipid bilayer, which contributes to stretch forces which result in opening of the channel. [7] While it is known that the lipid bilayer properties of cell membranes contribute to mechanosensation, it is yet unknown to the extent the protein interacts with the head groups of the lipids. [8] The mechanosensitivity of TREK-1 channels in a biological membrane was directly attributed to the generation of phosphatidic acid in a fast two step process (<3 ms). [9] Activation was based on a model where lipid micro domains, within the lipid bilayer, partition signaling molecules into separate compartments and mechanical mixing of the signals leads to the production of phosphatidic acid and downstream signaling. [10]

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 system and vestibular system.

Structure

The bundle of cilia that projects from the surface of the hair cell is the organelle 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. [11]

Function

When an event occurs which causes the bundle of cilia to deflect toward the taller side, ion channels open, and the inward current causes a depolarization of the cell. 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. [11] The sensitivity of cilia is primarily due to ciliary length. [12] The stereocilia of functional hair cells have the ability to convert mechanical deflections to neural signals. [13]

Current research

One aspect of hair cell mechanosensation that remains unknown is the stiffness 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. [14]

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. [14]

Channel blocking

FMI-43 is a dye which can be used to block mechanosensitive ion channels 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. [15]

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 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 biological and medical disciplines, recent discoveries[ citation needed ] 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." [16] Some primary cilia on epithelial cells in eukaryotes act as cellular antennae, providing chemosensation, thermosensation, and mechanosensation of the extracellular environment. These cilia then play a role in mediating specific signalling cues, including soluble factors in the external cell environment, a secretory role in which a soluble protein is released to have an effect downstream of the fluid flow, and mediation of fluid flow if the cilia are motile. [17] Some epithelial cells are ciliated, and they commonly exist as a sheet of polarized cells forming a tube or tubule with cilia projecting into the lumen.

Epithelial sodium channels (ENaC) that are specifically expressed along the entire length of cilia apparently serve as sensors that regulate fluid level surrounding the cilia. [18]

Important examples include motile cilia. A high-level-abstraction summary is that, "in effect, the cilium is a biological machine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines." [16] Flexible linker domains allow the connecting protein domain to recruit their binding partners and induce long-range allostery via protein domain dynamics. [19] This sensory and signalling role puts cilia in a central role for maintaining the local cellular environment and may be why ciliary defects cause such a wide range of human diseases. [20]

Neuropathic pain

Hyperalgesia 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.

Hyperalgesia

Hyperalgesia 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. [1]

Allodynia

Allodynia 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. [1]

See also

Related Research Articles

In physiology, nociception, also nocioception; from Latin nocere 'to harm/hurt') is the sensory nervous system's process of encoding noxious stimuli. It deals with a series of events and processes required for an organism to receive a painful stimulus, convert it to a molecular signal, and recognize and characterize the signal to trigger an appropriate defensive response.

<span class="mw-page-title-main">Sensory nervous system</span> Part of the nervous system responsible for processing sensory information

The sensory nervous system is a part of the nervous system responsible for processing sensory information. A sensory system consists of sensory neurons, neural pathways, and parts of the brain involved in sensory perception and interoception. Commonly recognized sensory systems are those for vision, hearing, touch, taste, smell, balance and visceral sensation. Sense organs are transducers that convert data from the outer physical world to the realm of the mind where people interpret the information, creating their perception of the world around them.

<span class="mw-page-title-main">Stimulus (physiology)</span> Detectable change in the internal or external surroundings

In physiology, a stimulus is a detectable change in the physical or chemical structure of an organism's internal or external environment. The ability of an organism or organ to detect external stimuli, so that an appropriate reaction can be made, is called sensitivity (excitability). Sensory receptors can receive information from outside the body, as in touch receptors found in the skin or light receptors in the eye, as well as from inside the body, as in chemoreceptors and mechanoreceptors. When a stimulus is detected by a sensory receptor, it can elicit a reflex via stimulus transduction. An internal stimulus is often the first component of a homeostatic control system. External stimuli are capable of producing systemic responses throughout the body, as in the fight-or-flight response. In order for a stimulus to be detected with high probability, its level of strength must exceed the absolute threshold; if a signal does reach threshold, the information is transmitted to the central nervous system (CNS), where it is integrated and a decision on how to react is made. Although stimuli commonly cause the body to respond, it is the CNS that finally determines whether a signal causes a reaction or not.

A mechanoreceptor, also called mechanoceptor, is a sensory receptor that responds to mechanical pressure or distortion. Mechanoreceptors are innervated by sensory neurons that convert mechanical pressure into electrical signals that, in animals, are sent to the central nervous system.

<span class="mw-page-title-main">Nociceptor</span> Sensory neuron that detects pain

A nociceptor is a sensory neuron that responds to damaging or potentially damaging stimuli by sending "possible threat" signals to the spinal cord and the brain. The brain creates the sensation of pain to direct attention to the body part, so the threat can be mitigated; this process is called nociception.

<span class="mw-page-title-main">Sensory neuron</span> Nerve cell that converts environmental stimuli into corresponding internal stimuli

Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded receptor potentials. This process is called sensory transduction. The cell bodies of the sensory neurons are located in the dorsal ganglia of the spinal cord.

<span class="mw-page-title-main">Hair cell</span> Auditory sensory receptor nerve cells

Hair cells are the sensory receptors of both the auditory system and the vestibular system in the ears of all vertebrates, and in the lateral line organ of fishes. Through mechanotransduction, hair cells detect movement in their environment.

<span class="mw-page-title-main">Dorsal root ganglion</span> Cluster of neurons in a dorsal root of a spinal nerve

A dorsal root ganglion is a cluster of neurons in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsal root ganglia.

<span class="mw-page-title-main">Stereocilia (inner ear)</span> Mechanosensing organelles of hair cells

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. The hair cells turn the fluid pressure and other mechanical stimuli into electric stimuli via the many microvilli that make up stereocilia rods. Stereocilia exist in the auditory and vestibular systems.

<span class="mw-page-title-main">Allodynia</span> Feeling of pain from stimuli which do not normally elicit pain

Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It is different from hyperalgesia, an exaggerated response from a normally painful stimulus. The term comes from Ancient Greek άλλος (állos) 'other', and οδύνη (odúnē) 'pain'.

Merkel nerve endings are mechanoreceptors, a type of sensory receptor, that are found in the basal epidermis and hair follicles. They are nerve endings and provide information on mechanical pressure, position, and deep static touch features, such as shapes and edges.

<span class="mw-page-title-main">Group C nerve fiber</span> One of three classes of nerve fiber in the central nervous system and peripheral nervous system

Group C nerve fibers are one of three classes of nerve fiber in the central nervous system (CNS) and peripheral nervous system (PNS). The C group fibers are unmyelinated and have a small diameter and low conduction velocity, whereas Groups A and B are myelinated. Group C fibers include postganglionic fibers in the autonomic nervous system (ANS), and nerve fibers at the dorsal roots. These fibers carry sensory information.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

Na<sub>v</sub>1.8 Protein-coding gene in the species Homo sapiens

Nav1.8 is a sodium ion channel subtype that in humans is encoded by the SCN10A gene.

Mechanosensitive channels (MSCs), mechanosensitive ion channels or stretch-gated ion channels are membrane proteins capable of responding to mechanical stress over a wide dynamic range of external mechanical stimuli. They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya. They are 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 (e.g. thirst). The channels vary in selectivity for the permeating ions from nonselective between anions and cations in bacteria, to cation selective allowing passage Ca2+, K+ and Na+ in eukaryotes, and highly selective K+ channels in bacteria and eukaryotes.

The neural encoding of sound is the representation of auditory sensation and perception in the nervous system. The complexities of contemporary neuroscience are continually redefined. Thus what is known of the auditory system has been continually changing. The encoding of sounds includes the transduction of sound waves into electrical impulses along auditory nerve fibers, and further processing in the brain.

TRPN is a member of the transient receptor potential channel family of ion channels, which is a diverse group of proteins thought to be involved in mechanoreception. The TRPN gene was given the name no mechanoreceptor potential C (nompC) when it was first discovered in fruit flies, hence the N in TRPN. Since its discovery in fruit flies, TRPN homologs have been discovered and characterized in worms, frogs, and zebrafish.

<span class="mw-page-title-main">Tip link</span>

Tip links are extracellular filaments that connect stereocilia to each other or to the kinocilium in the hair cells of the inner ear. Mechanotransduction is thought to occur at the site of the tip links, which connect to spring-gated ion channels. These channels are cation-selective transduction channels that allow potassium and calcium ions to enter the hair cell from the endolymph that bathes its apical end. When the hair cells are deflected toward the kinocilium, depolarization occurs; when deflection is away from the kinocilium, hyperpolarization occurs. The tip link is made of two different cadherin molecules, protocadherin 15 and cadherin 23. 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.

C tactile afferents are nerve receptors in mammalian skin that generally respond to nonpainful stimulation such as light touch. For this reason they are classified as ‘low-threshold mechanoreceptors’. As group C nerve fibers, they are unmyelinated and have slow conduction velocities. They are mostly associated with the sensation of pleasant touch, though they may also mediate some forms of pain. CT afferents were discovered by Åke Vallbo using the technique of microneurography.

A mechanoreceptor is a sensory organ or cell that responds to mechanical stimulation such as touch, pressure, vibration, and sound from both the internal and external environment. Mechanoreceptors are well-documented in animals and are integrated into the nervous system as sensory neurons. While plants do not have nerves or a nervous system like animals, they also contain mechanoreceptors that perform a similar function. Mechanoreceptors detect mechanical stimulus originating from within the plant (intrinsic) and from the surrounding environment (extrinsic). The ability to sense vibrations, touch, or other disturbance is an adaptive response to herbivory and attack so that the plant can appropriately defend itself against harm. Mechanoreceptors can be organized into three levels: molecular, cellular, and organ-level.

References

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