Mechanically-gated ion channels

Tethered model

When mechanical force is applied to tissue, it triggers stretching of the extracellular matrix and cell membranes, prompting also various compensatory cytoskeletal changes. Mechanically-gated channels are tethered to both extracellular accessory proteins and cytoskeleton-associated proteins. Based on the tethered model, forces are transmitted through these tethers from the extracellular matrix and cytoskeleton to the channel, leading to pore opening when the extracellular proteins are deflected to the appropriate direction. 

Initially, this model was favored for complex eukaryotic cells due to their intricate internal and external protein networks. However, recent studies suggest that certain mammalian ion channels can be activated by mechanical forces independently of connections with the extracellular matrix, resembling the force from lipids model.

Force from lipids model

The force from lipids model emerged from the identification and functional reconstitution of a prokaryotic mechanosensitive ion channel. It proposes that activation of the channel can arise from changes in the outer layer of the cell membrane, without necessitating additional structures. The lipid bilayer serves as an amphipathic compartment with a unique internal force-distribution profile. Physical stretching modifies this profile, inducing structural alterations in the channels, ultimately affecting their ion permeability.

Recent research indicates that the force from lipids model is also applicable to mammalian mechanically-gated ion channels.

Degenerin/Epithelial sodium ion channels (DEG/ENaC)

Degenerins are the first identified eukaryotic mechanically activated ion channels. They are sodium ion channels found in somatosensory neurons in C. elegans, a species of roundworm. The DEG/ENaC family of ion channels is characterized by genetic sequence similarities between degenerins and subunits of the mammalian epithelial sodium channels.

Transient receptor potential (TRP) channels

Transient receptor potential (TRP) channels form a family with characteristic evolutionarily conservation, classified into seven categories based on sequence homology.

TRP channels are essential to a wide range of sensory functions and respond to various stimuli including voltage, temperature, small molecules and mechanical forces. To date, three members of the family have been identified to be responsive to mechanical stimuli:

• TRPA: These channels are primarily associated with thermosensation in both invertebrates and vertebrates, but recent studies have identified their involvement in somatosensation as well.
• TRPN: Recent research findings show that TRPN channels are important for response to light touch and proprioception in invertebrates.
• TRPV: In Drosophila, TRPV channels are implicated in hearing, while in mammals, they are recognized as thermally activated ion channels. However, the ion channels responsible for mammalian hearing are yet to be fully explored.

Mechanically-gated potassium channels

The presence of mechanically-gated potassium channels introduces complexity to the traditional model of neuronal activation by mechanical force.

Unlike sodium channels, mechanically-gated potassium channels hyperpolarize the membrane potential, reducing the likelihood of an action potential. The physiological roles of these potassium channels in mechanotransduction remain poorly understood. Two members of this family of channels, namely potassium channel subfamily K members 2 and 4 (KCNK2 and KCNK4, respectively), have been detected in mammalian neurons. Their activity is modulated by a diverse array of stimuli, encompassing mechanical force, temperature and chemicals.

Under mechanical force the membrane stretch can activate mechanically-gated potassium channels following the force from lipids model.

Piezo channels

Piezo channels constitute a recently discovered family of mechanically-gated cation channels in eukaryotes, featuring Piezo1 and Piezo2 channels.

Piezo channels have a large size of approximately 2500 amino acids and encompass numerous transmembrane regions. Their distribution varies within tissues, playing a predominant role over other families of mechanically-gated ion channels due to their involvement in essential physiological processes of the mammals.

Beyond their involvement in the sensory nervous system, Piezo channels are implicated in various physiological processes, encompassing erythrocyte volume regulation, cell division and innate immunity. Furthermore, mutations in Piezo channels have been associated with several hereditary human diseases, such as autosomal recessive congenital lymphatic dysplasia, hereditary xerocytosis and an autosomal recessive syndrome characterized by muscular atrophy with perinatal respiratory distress.

Piezo1 channels

Piezo1 has diverse functions and is expressed in non-sensory tissues, such as the lung, urinary tract and cardiovascular system.

• Piezo1 is expressed in lung vascular endothelial cells and alveolar type II epithelial cells responsible for the adaptation to the increases in alveolar pressure and hydrostatic pressure.
• The role of Piezo1 in the urinary tract is to sense and respond to changes in both fluid flow and intraluminal pressure.
• In the cardiovascular system, shear stress was shown to activate the Piezo1 channel in endothelial cells, resulting in increased nitric oxide (NO) formation and vasodilation.

Piezo2 channels

Piezo2 channels play a pivotal role in sensory receptors, especially within the skin, muscles and internal organs. They are abundantly expressed in sensory neurons responsible for proprioception and touch, particularly in structures identified as Merkel cell neurite complexes.

Mechanosensitive sensory neurons

Mechanically-gated ion channels play a fundamental role in mechanosensitive sensory neurons responsible for the perception of light touch, vibration, pressure, proprioception and noxious mechanical stimuli. These specialized cells transform mechanical stimuli into electrical signals by initiating a cascade of action potentials. Broadly classified, these neurons fall into two categories: low threshold mechanoreceptors and high threshold mechanoreceptors.

Low threshold mechanoreceptors

Low threshold mechanoreceptors respond to external and internal mechanical stimuli. Proprioceptors are responsible for internal mechanical forces arising from the musculoskeletal system providing information about the position of the limbs and other body parts in space. Proprioceptors include muscle spindles, Golgi tendon organs and joint receptors. Mechanoreceptors for external stimuli are primarily located in the skin and respond to mild and harmless mechanical stimuli.

Four distinct mechanosensory end organs have been identified: Ruffini endings, Meissner corpuscles, Pacinian corpuscles and Merkel discs. 

High threshold mechanoreceptors

High threshold mechanoreceptors are part of the nociceptor family. Nociceptors respond to a variety of noxious stimuli, such as noxious chemical, cold, heat and mechanical stimuli. These neurons predominantly express TRPV and TRPA. TRPV responds to inflammation and pruritus, while TRPA is responsible for histamine-independent itch. The specifics for mechanical noxious stimuli receptors are to be found. High threshold mechanoreceptors mainly encompass free nerve endings, which extensively innervate the epidermis. Thin myelinated Aδ nerve fibers are believed to mediate rapid mechanical pain and exhibit responsiveness to noxious heat or cold stimuli, while thin unmyelinated C nerve fibers respond exclusively to mechanical stimuli and are characterized by slow conduction velocity.

Cochlear and vestibular hair cells

Mechanically-gated ion channels take part in the physiology of hearing and equilibrium located on specialized cells of the inner ear. These cells, known as hair cells, extend processes from their apical surface called stereocilia. The stereocilia are orderly arranged in rows of escalating height. The cohesive movement of the stereocilia is facilitated by lateral connections between individual stereocilia through structures known as tip links. The part of the membrane to which the tip links are attached is rich in mechanically-gated ion channels.

Movement of the stereocilia from the shortest to the tallest stereocilia due to mechanical stimuli leads to an incremental rise in mechanical tension. Consequently, mechanically-gated ion channels are activated, facilitating an influx of cations, especially K⁺ and Ca²⁺. This event depolarizes the membrane of the hair cell, giving rise to a receptor potential and leading to the release of neurotransmitters.

Conversely, movement of the stereocilia away from the tallest stereocilium results in the closure of these channels, inducing hyperpolarization in the hair cell and inhibition of the electrical activity.

The hair cells, depending on their physiology and location, are divided into cochlear and vestibular hair cells. Cochlear hair cells, located in the cochlea, transform the mechanical stimuli, in the form of sound vibrations, into electrical signals. These signals are subsequently relayed to the brain for interpretation. Vestibular hair cells detect head position and movement, transducing even minute displacements into receptor potentials.

Mechanosensitive endothelial and smooth muscle cells

Endothelial and smooth muscle cells sense mechanical stimuli that can affect the protein conformation of their cell membrane.

Piezo1 channels are expressed in endothelial and vascular smooth muscle cells and are activated by shear stress and stretching of the cell membrane associated with increased local blood flow and increased blood pressure. Piezo1 is required for regulating nitric oxide formation, vascular tone and blood pressure.

Alveolar epithelial and endothelial cells experience mechanical forces during respiration. Piezo1 channels are also expressed in lung vascular endothelial cells and alveolar type II epithelial cells responsible for the adaptation to the increases in alveolar pressure and hydrostatic pressure.
In the urinary system, mechanically-gated ion channels respond to bladder wall stretching. Piezo1, alongside TRPV4, contribute significantly to micturition by responding to bladder wall stretching, evoking Ca²⁺ influx and initiating the micturition reflex. 

Mechanosensitivity

Although the terms mechanically-gated ion channels and mechanosensitive channels might appear interchangeable, mechanosensitivity specifically denotes channels that alter their permeability in response to mechanical stress, even though they may predominantly respond to other types of stimuli. This broader category includes mechanosensitive voltage-gated channels and mechanosensitive ligand-gated channels.