Membrane Dynamics

How do mechanically-gated ion channels facilitate mechanotransduction?

Mechanotransduction relies on the ability of cells to convert mechanical cues, such as stretch or compression, to biochemical signals. One way this occurs is through the activity of mechanically-gated ion channels.

Calcium ions channels:

Physiologically, calcium ions (Ca2+) serve as important messengers in a range of signaling mechanisms. The effect of calcium influx is however, cell type dependent. In muscle cells, a Ca2+ mediated alteration of the membrane potential will induce contractions, while in neurons voltage gated Ca2+ channels will promote the release of neurotransmitters at the synapse.

From a mechanobiological perspective, Ca2+ ion channels are particularly important as they contribute to embryo development, stem cell differentiation and general mechanosensing processes. In these cases, substrate stiffness or other mechanical properties of the cellular microenvironment are the primary regulators of Ca2+ influx.

However, few ion channels have been confirmed as being mechanically regulated. Piezo1, together with the genetically related Piezo2, are evolutionarily conserved gated ion channels that have been shown to be regulated by mechanical stresses in the plasma membrane [1]. The activity of these mechanically-gated ion channels facilitates the transduction of mechanically activated cationic current in cells [2].

The influence of these proteins is far reaching. Neural stem cell differentiation was, for example, shown to be mediated by the activity Piezo1. When the ion channel was disrupted, either pharmacologically or genetically, neural stem cells differentiated towards astrocytes, rather than neurons [3]. Piezo1 has also been shown to play a role in the development of blood vessels during mouse embryogenesis [4]. In this case the ion channel is activated by shear stress induced through blood flow. Furthermore, a detrimental level of Ca2+ influx into primary articular chondrocytes was found to occur as a result of high levels of strain. This influx occurred through both Piezo1 and Piezo2. Although, in this case the high-strain was attributed to a Ca2+ mediated cell death, it was also shown that pharmacological inhibition of the Piezo proteins could minimize the effects of high levels of strain. This was proposed to be beneficial in the protection or repair of cartilage in diseases such as osteoarthritis [5]. Piezo2 has also been shown to be integral to the rapid mechanotransduction that facilitates the sense of touch. This has been proposed to result from Piezo2 mediated cross-talk that exists between low-threshold mechanoreceptors (LTMR) and Merkel cells [6]. An additional role for Piezo2 has been highlighted in metastatic breast cancer cells, where the protein was shown to maintain RhoA activity, and subsequently, stress fiber formation and orientation [7]. Deletion of the Piezo2 gene from LTMR cells derived from human embyonic stem cells lead to a loss in the ability of the cells to convert mechanical stimuli to electrical signals [8].

Cryo-electron microscopy of Piezo1 revealed that the channel assembles as a homotrimer, with a propeller-like architecture. The three extracellular ‘blades’ of the propeller surround the ion-conducting pore. These ‘blades’ are hypothesized to act as force sensors, and respond by regulating the opening and closing of the pore, providing a mechanosensitive mechanism for gating ion conduction. [9]

References

1. Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS, Kim SE, Schmidt M, Mathur J, Dubin AE, Montal M, and Patapoutian A. Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 2012; 483(7388):176-81. [PMID: 22343900]
2. Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ, Dubin AE, and Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 2010; 330(6000):55-60. [PMID: 20813920]
3. Pathak MM, Nourse JL, Tran T, Hwe J, Arulmoli J, Le DTT, Bernardis E, Flanagan LA, and Tombola F. Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells. Proc. Natl. Acad. Sci. U.S.A. 2014; 111(45):16148-53. [PMID: 25349416]
4. Ranade SS, Qiu Z, Woo S, Hur SS, Murthy SE, Cahalan SM, Xu J, Mathur J, Bandell M, Coste B, Li YJ, Chien S, and Patapoutian A. Piezo1, a mechanically activated ion channel, is required for vascular development in mice. Proc. Natl. Acad. Sci. U.S.A. 2014; 111(28):10347-52. [PMID: 24958852]
5. Lee W, Leddy HA, Chen Y, Lee SH, Zelenski NA, McNulty AL, Wu J, Beicker KN, Coles J, Zauscher S, Grandl J, Sachs F, Guilak F, and Liedtke WB. Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc. Natl. Acad. Sci. U.S.A. 2014; 111(47):E5114-22. [PMID: 25385580]
6. Woo S, Lumpkin EA, and Patapoutian A. Merkel cells and neurons keep in touch. Trends Cell Biol. 2014; 25(2):74-81. [PMID: 25480024]
7. Pardo-Pastor C, Rubio-Moscardo F, Vogel-González M, Serra SA, Afthinos A, Mrkonjic S, Destaing O, Abenza JF, Fernández-Fernández JM, Trepat X, Albiges-Rizo C, Konstantopoulos K, and Valverde MA. Piezo2 channel regulates RhoA and actin cytoskeleton to promote cell mechanobiological responses. Proc. Natl. Acad. Sci. U.S.A. 2018; 115(8):1925-1930. [PMID: 29432180]
8. Schrenk-Siemens K, Wende H, Prato V, Song K, Rostock C, Loewer A, Utikal J, Lewin GR, Lechner SG, and Siemens J. PIEZO2 is required for mechanotransduction in human stem cell-derived touch receptors. Nat. Neurosci. 2014; 18(1):10-6. [PMID: 25469543]
9. Ge J, Li W, Zhao Q, Li N, Chen M, Zhi P, Li R, Gao N, Xiao B, and Yang M. Architecture of the mammalian mechanosensitive Piezo1 channel. Nature 2015; 527(7576):64-9. [PMID: 26390154]