Open Access Articles- Top Results for Stretch-activated ion channel

Stretch-activated ion channel

Stretch-activated or stretch-gated ion channels are ion channels which open their pores in response to mechanical deformation of a neuron's plasma membrane. Also see mechanosensitive ion channels and mechanosensitive channels, with which they may be synonymous. Opening of the ion channels depolarizes the afferent neuron producing an action potential with sufficient depolarization.[1] Channels open in response to two different mechanisms: the prokaryotic model and the mammalian hair cell model.[2][3] Stretch-activated ion channels have been shown to detect vibration, pressure, stretch, touch, sounds, tastes, smell, heat, volume, and vision.[4][5][6] Stretch-activated ion channels have been categorized into three distinct "superfamilies": the ENaC/DEG family, the TRP family, and the K1 selective family. These channels are involved with bodily functions such as blood pressure regulation.[7] They are shown to be associated with many cardiovascular diseases.[3] Stretch-activated channels were first observed in chick skeletal muscles by Falguni Guharay and Frederick Sachs in 1983 and the results were published in 1984.[8] Since then stretch-activated channels have been found in cells from bacteria to humans as well as plants.


Stretch-activated ion channels are mechanotransducers which conduct ionic currents by responding to stress in the cell membrane. To be identified as stretch-activated, the ion channel must open and close in response to membrane tension.[7]Mechanotransduction, an electrical signal resulting from a mechanical stimulus, occurs via the opening of stretch-activated ion channels due to membrane deformation. The opening of these channels results in a non-specific ionic flow, which depolarizes the afferent nerve fiber, and may produce action potentials with sufficient depolarization.[1] The opening of these channels is central to a neuron’s response to pressure, often osmotic pressure and blood pressure, to regulate ionic flow in internal environments.[2] There are two mechanisms for which these channels open. The prokaryotic model suggests that stretch-activated channels open directly in response to force to the membrane, whereas the mammalian hair cell model involves a tether bound both to the channel and to the extracellular matrix or cytoskeleton. Force on the membrane then displaces the tether, creating tension which opens the channel.[2]


Stretch-activated ion channels are of use in the initial formation of an action potential from a mechanical stimulus, for example by the mechanoreceptors in an animal's vibrissae (whiskers).

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.[1]

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.[4][5] They are expressed in sensory modalities including taste, hearing, smell, heat sensation, volume control, and vision.[2][3][6] 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 contractility.[2][6] In addition to these functionalities, stretch-activated ion channels have also been found to be involved with balance and proprioceptive sensation.[2]

Examples in functionality

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.[9] 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.[3] 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.[2] In the body, a possible role in myoblast development has been described.[10] 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.[11] These channels also play a role in sensing vibration and pressure via activation of Pacinian corpuscles in the skin.[12]


Stretch-activated ion channels are one of the three main types of ionotropic receptors, or channel-linked receptors. These channels open when mechanical forces of stretch or pressure is applied to the channels, causing them to undergo a conformational change. This change allows ions to pass through.[13] The channels may also be pulled open due to tension on the membrane itself.[13] Opening the channels allows ions to which they are permeable to flow down their electrochemical gradients into or out of the cell, causing a change in membrane potential.

All types of stretch-activated ion channels respond to mechanical stimuli with a similar mechanism. A stimulus resulting from a deformation of the capsule on the afferent neuron causes a stretch in the membrane. This mechanical deformation causes stretch-sensitive channels to have an increased probability of opening. A depolarization of the afferent nerve fiber occurs as the stretch-activated cation channel opens. An action potential fires if the cell is depolarized above threshold and it propagates to the CNS.[1] The sensory stimuli that excite stretch-activated channels are regulated by Ab and Aa nerve fibers. These fibers have low thresholds and originate from mechanosensory neurons in the dorsal root ganglion.[4] ). 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.[7]

Regulation 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.[4]

Two different mechanisms have been found to open stretch-activated ion channels: 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.[4] All known stretch-activated ion channels in prokaryotic cells have been found to be opened by direct deformation of the lipid bilayer membrane.[2] 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.[2]

Experiments in channel regulation

Through experiments performed on the cytoskeleton and extra-cytoplasmic matrix of stretch-activated ion channels, these structures have been shown to play significant roles in mechanotransduction.[4] In one such experiment on adult heart cells, whole cell recordings were taken on cells being squeezed with two pipettes at 1 Hz/1 um. This squeezing produced no current until five minutes in when a large depolarization was observed. Hereafter, the cell became extremely responsive to every compression and gradually decreased sensitivity over the next few minutes.[7] Researchers hypothesized that, initially, the cytoskeleton was buffering the mechanical deformation of the squeezing from the channel. The depolarization at five minutes was the cytoskeleton snapping which subsequently caused the channel to sense the mechanical deformations and thereby respond to the stimuli. Researchers believe that over the few minutes where the channel repaired itself the cytoskeleton must be repairing itself and newly adapting to the squeezing stimuli.[7]


ENaC/DEG superfamily


There are six known ASIC subunits, ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, and ASIC4, which have two transmembrane domains, extracellular and intracellular loops, and C and N termini. These ASIC subunits likely form tetramers with varying kinetics, pH sensitivity, tissue distribution, and pharmacological properties.[4]

TRP superfamily

There are seven subfamilies within the TRP superfamily: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin), and TRPN (NOMPC-like).[4] TRP proteins typically consist of six transmembrane domains, S1, S2, S3, S4, S5, and S6, with a pore between S5 and S6. These contain intracellular N and C termini, which form tetramers[9] and vary in length and domain.[4] Within the channel there are ankyrins, which are structural proteins that mediate protein-protein interactions, and are thought to contribute to the tether model of stretch-activated channel opening. NOMPC, identified in D. melanogaster mechanotransduction and a member of the TRPN subfamily, contains a relatively high number of ankyrins.[2]

K1-selective superfamily

K2P channels consist of six subfamilies and contain four transmembrane domains, which form two pores each between domains 1–2 and 3–4. K2P channels also contain a short N terminal domain and a C terminal which varies in length. There is also a large extracellular linker region between domain 1 and the first pore formed between domains 1–2.[4]


TRP channels are typically non-selective, although a few are selective for calcium or hydrated magnesium ions, and are composed of integral membrane proteins. Although many TRP channels are activated by voltage change, ligand binding, or temperature change,[4] some TRP channels have been hypothesized to be involved in mechanotransduction.[3] Some examples are TRPV4, which mediates mechanical load in a variety of tissues, including the liver, heart, lung, trachea, testis, spleen, salivary glands, cochlea, and vascular endothelial cells,[3] as well as TRPC1 and TRPC6, which are involved in muscle mechanosensation. TRPC1 is expressed in the myocytes of the heart, arteries, and skeletal muscle. TRPC1 is widely considered to be a non-selective “store-operated ion channel” (SOC) involved in the calcium influx following calcium depletion of the endoplasmic reticulum of the cell.[15] TRPC6 is a calcium-permeable non-selective cation channel expressed in the cardiovascular system. TRPC6 is potentially a sensor of mechanically and osmotically induced membrane stretch, and is possibly directly gated by membrane tension.[15] Other examples include TREK-1 and TRAAK which are found in mammalian neurons and are classified as potassium channels in the tandem pore domain class[16][17] and "MID-1" (also known as "MCLC" or CLCC1.)[18][19]

The six K2P channel subfamilies are regulated by various physical, cellular, and pharmacological stimulants, including membrane stretch, heat, pH change, calcium flux, and protein kinases.[4]

Clinical relevance

Stretch-activated ion channels perform important functions in many different areas of our body. Pressure-dependent myogenic constriction resistance arteries require these channels for regulation in the smooth muscle of the arteries.[5] They have been found to be used for volume sensing in animals and blood pressure regulation.[7] Bacteria have been shown to relieve hydrostatic pressure through MscL and MscS channels.[7]

Pathologies associated with stretch-activated ion channels

Stretch-activated ion channels have been correlated with major pathologies. Some of these pathologies include cardiac arrhythmia (such as atrial fibrillation),[7] cardiac hypertrophy, Duchenne muscular dystrophy,[5] and other cardiovascular diseases.[3]

Blocking stretch-activated ion channels

Gd2+ and lanthanides have been shown to block stretch-activated ion channel function. GsMTx4 has been shown to inhibit these channels from the extracellular side, but it does not inhibit all stretch-activated ion channels and particularly has no effect on 2p channels.[7]

See also


  1. ^ a b c d Purves, Dale. (2004). Neuroscience. Sunderland, Mass.: Sinauer Associates. pp. 207–209. ISBN 978-0-87893-725-7. 
  2. ^ a b c d e f g h i j López-Larrea, Carlos (2011). Sensing in Nature. New York: Springer Science+Business Media. ISBN 978-1-4614-1703-3. 
  3. ^ a b c d e f g Yin J, Kuebler WM (2010). "Mechanotransduction by TRP channels: general concepts and specific role in the vasculature". Cell Biochem Biophys 56 (1): 1–18. PMID 19842065. doi:10.1007/s12013-009-9067-2. 
  4. ^ a b c d e f g h i j k l Del Valle ME, Cobo T, Cobo JL, Vega JA (August 2012). "Mechanosensory neurons, cutaneous mechanoreceptors, and putative mechanoproteins". Microsc. Res. Tech. 75 (8): 1033–43. PMID 22461425. doi:10.1002/jemt.22028. 
  5. ^ a b c d Patel A, Sharif-Naeini R, Folgering JR, Bichet D, Duprat F, Honoré E (August 2010). "Canonical TRP channels and mechanotransduction: from physiology to disease states". Pflugers Arch. 460 (3): 571–81. PMID 20490539. doi:10.1007/s00424-010-0847-8. 
  6. ^ a b c Martinac B (2011). "Bacterial mechanosensitive channels as a paradigm for mechanosensory transduction". Cell. Physiol. Biochem. 28 (6): 1051–60. PMID 22178995. doi:10.1159/000335842. 
  7. ^ a b c d e f g h i Sachs F (2010). "Stretch-activated ion channels: what are they?". Physiology (Bethesda) 25 (1): 50–6. PMC 2924431. PMID 20134028. doi:10.1152/physiol.00042.2009. 
  8. ^ Guharay F, Sachs F (July 1984). "Stretch-activated single ion channel currents in tissue-cultured embryonic chick skeletal muscle". J. Physiol. (Lond.) 352: 685–701. PMC 1193237. PMID 6086918. doi:10.1113/jphysiol.1984.sp015317. 
  9. ^ a b Bianchi L (December 2007). "Mechanotransduction: touch and feel at the molecular level as modeled in Caenorhabditis elegans". Mol. Neurobiol. 36 (3): 254–71. PMID 17955200. doi:10.1007/s12035-007-8009-5. 
  10. ^ Formigli L, Meacci E, Sassoli C, Squecco R, Nosi D, Chellini F, Naro F, Francini F, Zecchi-Orlandini S (May 2007). "Cytoskeleton/stretch-activated ion channel interaction regulates myogenic differentiation of skeletal myoblasts". J. Cell. Physiol. 211 (2): 296–306. PMID 17295211. doi:10.1002/jcp.20936. 
  11. ^ Zhao Y, Yamoah EN, Gillespie PG (December 1996). "Regeneration of broken tip links and restoration of mechanical transduction in hair cells". Proc. Natl. Acad. Sci. U.S.A. 93 (26): 15469–74. PMC 26428. PMID 8986835. doi:10.1073/pnas.93.26.15469. 
  12. ^ Bell J, Bolanowski S, Holmes MH (January 1994). "The structure and function of Pacinian corpuscles: a review". Prog. Neurobiol. 42 (1): 79–128. PMID 7480788. doi:10.1016/0301-0082(94)90022-1. 
  13. ^ a b Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed., Pages 113–114. McGraw-Hill, New York (2000). ISBN 0-8385-7701-6
  14. ^ a b Lumpkin EA, Caterina MJ (February 2007). "Mechanisms of sensory transduction in the skin". Nature 445 (7130): 858–65. PMID 17314972. doi:10.1038/nature05662. 
  15. ^ a b Patel A, Sharif-Naeini R, Folgering JR, Bichet D, Duprat F, Honoré E (2010). "Canonical TRP channels and mechanotransduction: from physiology to disease states". Pflugers Arch 460 (3): 571–81. PMID 20490539. doi:10.1007/s00424-010-0847-8. 
  16. ^ Maingret F, Fosset M, Lesage F, Lazdunski M, Honoré E (January 1999). "TRAAK is a mammalian neuronal mechano-gated K+ channel". J. Biol. Chem. 274 (3): 1381–7. PMID 9880510. doi:10.1074/jbc.274.3.1381. 
  17. ^ Patel AJ, Honoré E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M (August 1998). "A mammalian two pore domain mechano-gated S-like K+ channel". EMBO J. 17 (15): 4283–90. PMC 1170762. PMID 9687497. doi:10.1093/emboj/17.15.4283. 
  18. ^ Nagasawa M, Kanzaki M, Iino Y, Morishita Y, Kojima I (2001). "Identification of a novel chloride channel expressed in the endoplasmic reticulum, golgi apparatus, and nucleus". J. Biol. Chem. 276 (23): 20413–20418. PMID 11279057. doi:10.1074/jbc.M100366200. 
  19. ^ Ozeki-Miyawaki C, Moriya Y, Tatsumi H, Iida H, Sokabe M (2005). "Identification of functional domains of Mid1, a stretch-activated channel component, necessary for localization to the plasma membrane and Ca2+ permeation". Exp. Cell Res. 311 (1): 84–95. PMID 16202999. doi:10.1016/j.yexcr.2005.08.014.