Classification of Mechanoreceptors and Their Physiological Importance: History
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Contributor:
Álvaro Otero-Sobrino
,
Pablo Blanco-Carlón
,
Miguel Ángel Navarro-Aguadero
,
Miguel Gallardo
,
Joaquín Martínez-López
,
María Velasco-Estévez

Mechanosensitive ion channels comprise a broad group of proteins that sense mechanical extracellular and intracellular changes, translating them into cation influx to adapt and respond to these physical cues. All cells in the organism are mechanosensitive, and these physical cues have proven to have an important role in regulating proliferation, cell fate and differentiation, migration and cellular stress, among other processes. Indeed, the mechanical properties of the extracellular matrix in cancer change drastically due to high cell proliferation and modification of extracellular protein secretion, suggesting an important contribution to tumor cell regulation.

  • mechanoreceptors
  • ion channels
  • TRP
  • PIEZO
  • immunity
  • cancer

1. Introduction

Mechanosensation is the ability of cells to recognize mechanical and physical forces, and it is essential for many physiological functions, playing a pivotal role in both health and disease. In line with this, it has been shown that there are dramatic intratumoral mechanical changes at the onset of many types of cancer [1]. Cancer cells are constrained by high mechanical cues due to the increased extracellular matrix (ECM) stiffness and the high interstitial pressure of the tumor. Such forces can stimulate the proliferation, migration, and even invasion of cancer cells through mechanosensitive ion channels, thus playing an important role in both the onset and progression of the tumor [2][3].
Mechanosensitive ion channels are a family of pore-forming proteins crucial for detecting intra- and extracellular mechanical cues (e.g., pressure, stretch or shear flow). These channels then translate mechanical cues into biochemical signals in a process termed mechanotransduction, allowing the cell to adapt and respond to mechanical forces [4][5]. Upon mechanical stimuli, the cation influx into the cytoplasm can mediate a myriad of cell responses such as cell growth, migration, adhesion, morphogenesis, gene expression, fluid homeostasis and vesicular transport [6].
Understanding the role of mechanoreceptors in the different cancer types, as well as in the immune system and cancer immunity, is vital to fully uncovering the importance of the mechanical properties of the tumor environment.

2. Classification of Mechanoreceptors and Their Physiological Importance

Árnadottir and Chalfie defined the criteria for ion channels to act as mechanoreceptors [7]. First, the channel must be expressed in a mechanosensory organ. Second, the loss of the channel is necessary but insufficient to end the signal transduction. Third, the genetic modification of the channel should change the mechanical response. Lastly, channel heterologous expression must reveal that it can be physically gated. However, new evidence about mechanosensitive ion channels has redefined these criteria and established four different families of mechanoreceptor channels in mammals [8]: epithelial sodium channel/degenerin (ENaC/DEG), transient receptor potential channel (TRP), two-pore domain potassium channel (K2P) and PIEZO channels.

2.1. The Epithelial Sodium Channel/Degenerin Superfamily

The ENaC/DEG family represents a class of ion channels that are present in animals with specialized organ functions and have functional heterogeneity depending on their tissue distribution. In humans, ENaC and acid-sensing ion channels (ASIC) can be found inside this family [9]. Both have a trimeric structure with two transmembrane segments and a large extracellular region [10] (Figure 1A), but they display different gating mechanisms [10][11].
ENaC channels are encoded by four paralogous genes (SCNN1A, SCNN1B, SCNN1D and SCNN1G) that encode the subunits α, β, γ and δ, respectively [12]. These channels are expressed on the apical plasma membrane of epithelial cells in several organs, such as the kidney, lung, salivary glands, skin, placenta and colon, and play a central role in Na+ absorption, maintenance of water-salt homeostasis, and blood pressure control. Depending on the tissue where ENaC is expressed, its physiological role varies. For instance, in the kidney, filtered Na+ exits the collecting duct’s urinary space through ENaC, restricting the amount of salt that can be reabsorbed [13]; in the colon, ENaC also participates in Na+ reabsorption [14], whereas in the lungs, ENaC is a key regulator of airway surface liquid clearance [15].
On the other hand, ASICs are primarily proton-gated cation channels that can be triggered by nonproton ligands at physiological pH levels and activated by a decrease in extracellular pH below 7.0 [11]. They also have a mechanosensitive role in colon ganglia cells, nerve terminals of the aortic arch and the bladder [16]. ASIC proteins, encoded by four genes (ACCN1, ACCN2, ACCN3 and ACCN4), form at least six subtypes of channels. Activation of ASICs triggers Na+ influx but also exhibits calcium permeability, acquiring important functions in learning and memory [17].

2.2. Transient Receptor Potential Channel Family

Transient receptor potential (TRP) channels are nonselective cation channels that play an important role in Ca2+ signaling. TRPs act as sensors of light, touch or mechanical pain [18], leading to membrane depolarization through Ca2+ influx. They form tetrameric cation-selective complexes of either identical or distinct subunits, each with six transmembrane domains with both the N- and C-termini in the intracellular compartment [19] (Figure 1B).
In mammals, the TRP family is composed of 28 members distributed in six subfamilies [19][20]: TRPC (canonical channels), TRPV (vanilloid), TRPA (ankyrin), TRPM (melastatin), TRPML (mucolipin) and TRPP (polycystin). The TRPC, TRPV and TRPA subfamilies contain ankyrin repeat motifs present in tandem copies that confer elastic properties, playing a key role in mechanosensing [21]. Most TRPs are expressed in the plasmatic membrane, but some of them also exert their function at intracellular membranes, playing a role in endolysosomal system regulation [22][23].
TRPC members play important roles in different tissues, including the cardiovascular system, skeletal muscles, lung, kidneys, salivary glands, reproductive system, immune system, and nervous system, as reviewed in [24][25].
In mammals, a sole member (TRPA1) composes the TRPA subfamily. The expression of this channel has been described in several cell types, such as sensory neurons, epithelial cells, melanocytes and keratinocytes, and it can be activated not only by mechanical cues but also by pH changes, thermal changes and different ligands, such as cholesterol or nicotine [26].
Finally, inside the TRPV subfamily, TRPV1–4 are nonselective cation channels that are modestly permeable to Ca2+, while TRPV5 and TRPV6 are highly selective Ca2+ channels. All of them are widely expressed in mammals, such as neural tissue, kidneys, liver, immune system, heart, smooth muscle, skin, lung and placenta [27].

2.3. Two-Pore-Domain Potassium Channel Family

The two-pore-domain potassium channels (K2P) are a diverse family of K+ selective channels encoded by fifteen different genes [28] and regulated by mechanical cues as well as other stimuli such as anesthetics and antidepressant agents [29][30], neurotransmitters, posttranslational modifications or temperature [31]. K2Ps are classified into six different subfamilies (TWIK, TREK, TASK, TALK, THIK and TRESK) according to their sequence similarity and functional characteristics [32]. Plasma membrane tension, complemented by other mechanical factors such as protein–protein interactions and cytoskeletal modulation, directly regulates TREK subfamily members [32][33].
Their structure differs from other K+ channels, as each K2P subunit contains four transmembrane domains (M1–M4 domains) and two pore-forming domains (P domains), with the N- and C-terminal sides at the cytoplasmic side (Figure 1C). They act as homodimers, as K2P needs four P domains to constitute the K+ selective filter [32][34].
K2P channels have a key role in the nervous system, heart and muscles by controlling membrane resting potential and excitability [35][36]. However, they exert important functions in non-excitable tissues, such as the pancreas, by controlling glucagon release [37], surfactant integrity in the lungs [38], and the proliferation and cytolytic functions of natural killer cells [39].

2.4. PIEZO Channel Family

The PIEZO family comprises mechanoreceptors Piezo1 and Piezo2, also known as FAM38A and FAM38B, respectively. Piezo1 was first identified and characterized in a mouse neuroblastoma cell line by Coste and colleagues [40], and they later identified Piezo2 by sequence homology. They are both nonselective Ca2+ channels that are highly conserved across species and expressed in most tissues of organisms, giving an idea of their biological importance.
PIEZO proteins have an unusually large size compared to other ion channels. They have an overall size of over 2500 amino acids, with a large number of transmembrane regions [40]. Mouse Piezo1 and Piezo2 channels have been structurally characterized by cryoEM [41][42]. Both channels have a similar structure, comprising a homotrimer forming a three-blade propeller plus an extracellular cap [41][42] (Figure 1D).
It is important to note that, while most of the mechanosensitive channels described above exhibit multiple activation mechanisms, the only channels that are principally activated by mechanical stimuli are the PIEZO channels [43][44]. However, it has been shown that although their main activation cue is mechanical stimuli, PIEZO channels can also be modulated by voltage [45].
Ijms 24 13710 g001
Figure 1. Top view structures of (A) hASIC1a [46], (B) hTRPV4 [47], (C) hTRAAK [48], and (D) mPiezo1 [41]. Structures obtained from the Protein Data Bank (PDB IDs 7CFS, 8T1B, 3UM7 and 5Z10), respectively.

This entry is adapted from the peer-reviewed paper 10.3390/ijms241813710

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