Type of membrane proteins
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.
All organisms, and apparently all cell types, sense and respond to mechanical stimuli. MSCs function as mechanotransducers capable of generating both electrical and ion flux signals as a response to external or internal stimuli. Under extreme turgor in bacteria, non selective MSCs such as MSCL and MSCS serve as safety valves to prevent lysis. In specialized cells of the higher organisms, other types of MSCs are probably the basis of the senses of hearing and touch and sense the stress needed for muscular coordination. However, none of these channels have been cloned. MSCs also allow plants to distinguish up from down by sensing the force of gravity. MSCs are not pressure-sensitive, but sensitive to local stress, most likely tension in the surrounding lipid bilayer.
History.
Mechanosensitive channels were discovered in 1983 in the skeletal muscle of embryonic chicks by Falguni Guharay and Frederick Sachs. They were also observed (pub. 1986) in Xenopus oocytes, and frequently studied since that time. 
Since then, MSCs have been found in cells from bacteria to humans: they are now known to be present in all three domains of life (Archaea, Bacteria and Eukarya, incl. plants and fungi). In the decades since the discovery of MS, the understanding of their structure and function has increased greatly, and several have been cloned. Specifically, the cloned eukaryotic mechanosensitive channels include the K+ selective 2P domain channels and the recently cloned cation selective PIEZO family (PIEZO1 and PIEZO2).
Classification.
MSCs can be classified based on the type of ion to which they are permeable:
Broadly, most MSCs can be classified as lipid-gated channels.
Functions.
For a protein to be considered mechanosensitive, it must respond to a mechanical deformation of the membrane. Mechanical deformations can include changes in the tension, thickness, or curvature of the membrane. Mechanosensitive channels respond to membrane tension by altering their conformation between an open state and a closed state. One type of mechanically sensitive ion channel activates specialized sensory cells, such as cochlear hair cells and some touch sensory neurons, in response to forces applied to proteins.
Stretch-activated ion channels are required for the initial formation of an action potential from a mechanical stimulus, for example by the mechanoreceptors in vibrissae (whiskers) of some animals such as rodents.
Afferent nerve fibers responsible for sensory stimulus detection and feedback are especially sensitive to stimulation. This results from the specialized mechanoreceptor cells that are superimposed upon the afferent nerve fibers. Stretch-activated ion channels are located on these mechanoreceptor cells and serve to lower the action potential threshold, thus making the afferent nerves more sensitive to stimulation. Afferent nerve endings without mechanoreceptor cells are called free nerve endings. They are less sensitive than the encapsulated afferent fibers and generally function in the perception of pain.
Stretch-activated ion channels are responsible for many bodily functions in mammals. In the skin they are responsible for sensing vibration, pressure sensation, stretch, touch, and light touch. They are expressed in sensory modalities including taste, hearing, smell, heat sensation, volume control, and vision. They can also regulate internal functions of our body including, but not limited to, osmotic pressure in cells, blood pressure in veins and arteries, micturition, and heart electrophysiology and contractility. In addition to these functionalities, stretch-activated ion channels have also been found to be involved with balance and proprioceptive sensation.
Channels that have traditionally been known as just "voltage-" or "ligand-gated" have also been found to be mechanically sensitive as well. Channels exhibit mechanical sensitivity as a general property. However, mechanical stress affects various types of channels in different ways. Voltage and ligand gated channels can be modified slightly by mechanical stimulation, which might change their responsiveness or permeability slightly, but they still respond primarily to voltage or ligands, respectively.
Examples.
The different families of stretch-activated ion channels are responsible for different functions around the body. The DEG/ENaC family consists of two subgroups: the ENaC subfamily regulates Na+ reabsorption in kidney and lung epithelia; the ASIC subfamily is involved in fear conditioning, memory formation, and pain sensation. The TRP superfamily of channels are found in sensory receptor cells that are involved in heat sensation, taste, smell, touch, and osmotic and volume regulation. MscM, MscS, and MscL channels (mechanosensitive channels of mini, small, and large conductance) regulate osmotic pressure in cells by releasing intracellular fluid when they become too stretched. In the body, a possible role in myoblast development has been described. Furthermore, mechanically gated ion channels are also found in the stereocilia of the inner ear. Sound waves are able to bend the stereocilia and open up ion channels leading to the creation of nerve impulses. These channels also play a role in sensing vibration and pressure via activation of Pacinian corpuscles in the skin.
Transduction mechanisms.
There are two different types of stretch-activated channels between which it is important to distinguish: mechanically gated channels, which are directly influenced by mechanical deformations of the membrane, and mechanically sensitive channels, which are opened by second messengers released from the true mechanically gated channel.
Mechanical deformations in the cell membrane can increase the probability of the channels opening. Proteins of the extracellular matrix and cytoskeleton are tethered to extra - and intra-cytoplasmic domains, respectively, of the stretch-activated ion channels. Tension on these mechanosensory proteins causes these proteins to act as a signaling intermediate, resulting in the opening of the ion channel. All known stretch-activated ion channels in prokaryotic cells have been found to be opened by direct deformation of the lipid bilayer membrane. Channels that have been shown to exclusively use this mechanism of gating are the TREK-1 and TRAAK channels. In studies using mammalian hair cells, the mechanism that pulls on proteins tethered from the intra- and extra-cytoplasmic domain of the channel to the cytoskeleton and extracellular matrix, respectively, is the most likely model for ion channel opening.
Mechanical deformation of the cell membrane can be achieved by a number of experimental interventions, including magnetic actuation of nanoparticles. An example of this is the control of calcium influx of axons and boutons within neural networks. ;ref name="doi:10.1021/acs.nanolett.6b04200" ;. ;/ref ; Note that this is not an indication of 'magnetic stimulation' of mechanosensitive channels.
Gating mechanism.
Although MS vary in many aspects, structures and functions, all the MS studied to date share an important feature: in a process called "gating", they all open in a pore-like manner when protein channels are activated by a mechanical stimulus. There are currently two models of the gating process that explain how membrane-activated ion channels open.
Lipid bilayer Tension or stretch model: In this model tension in the lipid bilayer triggers conformational changes, thus leading to the opening of the channels. The tension perceived by the protein comes from the lipids. It has been demonstrated that the tension/stretch profile in the lipid bilayer is originated by membrane curvature and bilayer-protein hydrophobic mismatch.
Spring-like Tether model: In this model a spring-like tether is attached directly to the MS channel and can be present in either the cytoskeleton or the extracellular matrix linking these elements together. When external stimuli deflect the tether the displacement opens the channel. This particular mechanism has been demonstrated to be the responsible for gating hair cells which are responsible for hearing in vertebrates.
Bacterial MSCs.
Bacterial MS channels were first discovered by patch-clamp experiments in E. coli. They have been classified based on their conductance as mini (MscM), small (MscS) and large large (MscL)). These channels function in tandem-mode and are responsible of turgor regulation in bacteria; when activated by changes in the osmotic pressure. MscM is activated first at really low pressures followed by MscS, and finally MscL being the last chance of survival during osmotic shock. Their task was demonstrated when bacteria missing both MscS and MscL were lysed after exposure to osmotic downshocks.
MscS: Small conductance mechanosensitive channel.
The main conductance is 1nS in buffer solution. Channel-proteins have been found in gram-positive and gram-negative bacteria, archaea and plants. MscS channel was found after studies in "E. coli" spheroplasts. The identification of the gene family necessitated for MS of small conductance was as two different channels. YggB encoding MscS and KefA encoding MscK in "E. coli" further confirm its role osmotic regulation. Mutagenesis studies showed that when both genes YggB and KefA were deleted MscS lost its function, but maintain MscL and MscM, but mutants deficient of YggB and MscL showed that the function of those channel is to open in respond to pressure range right before cell rupture.
The 3D structure of this channel at closed state was elucidated after the crystallography study by Bass et al. which showed that at resolution of 3.9 Å this 31kDa protein is an homoheptamer forming a channel with 80 Å of diameter and 120 Å in length, each subunit contains three transmembrane domains (TM1, TM2, and TM3) with the N-terminal facing the periplasm and the C-terminal embedded in the cytoplasm. The TM3 is highly conserved in MscS family and it is thought to play an important role in MS prokaryotic gating. MscS is a small protein composed of 286 amino acid residues activated by both tension in the lipid bilayer and voltage; in 2002 Vasquez et al. detailed this process and showed that during the change from closed state to open state the TM1 tilt and rotate making TM2 being exposed to the membrane and the TM3 helices expand, tilt, and rotate. During the rearrangement the confined part of the pore was measured as 11 Å, and water molecules were more accessible to the TM3. The two transmembrane domains are in continuous contact with the lipid bilayer and are thought to be the sensor for the tension in the lipid bilayer as well as sensor for voltage because of the three arginine residues present in those domains.
Although MscS is activated by voltage it has been demonstrated that, voltage itself is insufficient to open the channel, thus functioning in a cooperative manner with the channel. The more positive voltage, the higher the probabilities of opening the channel as long as pressure over the threshold is still applied in the system; the performance of this channel at higher voltage has not been completely understood. MscS has a small affinity for negative ions including Cl-, and glutamate.
MscL: Large conductance mechanosensitive channel.
In bacteria MscL was the first MS channels cloned and sequenced, and is by far one of the most studied channels. The gene encoding MscL protein is trkA and it is located in the inner membrane of the "E. coli". The protein is 17 KDa, and consists of 136 amino acids; mostly hydrophobic residues resulting in two hydrophobic segments, however molecular weight of the functional channel is presumed to be 60-70 KDa from gel filtration experiments, suggesting oligomerization. As a common feature no cysteines residues are present in this channel.
In 1998 the homolog MscL from mycobacterium tuberculosis Tb-MscL was elucidated at closed state by X ray crystallography at 3.5 Å resolution. The protein is a homopentamer composed mostly of helical regions trans orientation of the helices with respect to the bilayer, with two domains: the cytoplasmic and the transmembrane. The channel is 85 Å in length, 35 Å and 50 Å for the cytoplasmic transmembrane domain respectively and 50 Å in diameter. The helices cross the membrane twice with both the C-terminal and the N-terminal, thus having two transmembrane domains TM1 and TM2 being TM1 the most conserved region among MscL proteins especially at the N-terminal region. It is located in the cytoplasm and forms a α-hydrophobic helix called S1; the region between the transmembrane domains form a loop that is divided into two regions: S2 a glycine-proline rich region and S3 a short helical section. The secondary structure of the protein is resistant to thermal denaturation still in the presence of SDS.
During the activation of