Trends in Neurosciences
Volume 35, Issue 8, August 2012, Pages 477-486
Journal home page for Trends in Neurosciences

Review
Sensing pressure with ion channels

https://doi.org/10.1016/j.tins.2012.04.002Get rights and content

Opening of stretch-activated ion channels (SACs) is the earliest event occurring in mechanosensory transduction. The molecular identity of mammalian SACs has long remained a mystery. Only very recently, Piezo1 and Piezo2 have been shown to be essential components of distinct SACs and moreover, purified Piezo1 forms cationic channels when reconstituted into artificial bilayers. In line with these findings, dPiezo was demonstrated to act in the Drosophila mechanical nociception pathway. Finally, the 3D structure of the two-pore domain potassium channel (K2P), TRAAK [weakly inward rectifying K+ channel (TWIK)-related arachidonic acid stimulated K+ channel], has recently been solved, providing valuable information about pharmacology, selectivity and gating mechanisms of stretch-activated K+ channels (SAKs). These recent findings allow a better understanding of the molecular basis of molecular and cellular mechanotransduction.

Introduction

Mechanotransduction concerns the biological responses to mechanical stimuli 1, 2, 3, 4, 5, 6. The earliest event in mechanosensory transduction is a change in membrane potential of the cell resulting from the opening of mechanosensitive channels. These channels can be either non-selective depolarizing (i.e. SACs; see Glossary), permeable to Na+, K+ and Ca2+, or hyperpolarizing channels selective for K+ (i.e. SAKs) (Figure 1). Specialized mechanosensory cells respond to mechanical stimuli within micro- to milliseconds, suggesting a direct activation of the transduction channel by force (Box 1). For instance, in the cochlea, the deflection of the hair-cell stereocilia opens non-selective channels and this mechanism (which is the basis of hearing) can operate at a frequency of 20 kHz or even higher [3].

Over the years, in light of genetic findings obtained with invertebrates, several molecular candidates have been put forward in mammals, such as transient receptor potential (TRP) channels and acid-sensing ion channels (ASICs) (1, 2, 7, 8, 9 for reviews). However, direct pressure activation of these mammalian depolarizing channels could never be convincingly demonstrated in heterologous expression systems. Only very recently, two proteins, termed Piezo1 and Piezo2, have been identified as essential components of distinct SACs in mammalian cells [10]; such findings have shed light on the molecular mechanisms of cellular mechanotransduction [10]. By contrast, the molecular identity of SAKs has been known for over a decade ([11] for review). Very recently, a 3D structure of these channels has been solved, providing new molecular information about permeation, pharmacology, and gating mechanisms, which may also apply to other types of mammalian SACs 12, 13.

In the first part of this review we will discuss the information available from invertebrates about the ion-channel subunits involved in mechanotransduction, as well as their mechanism of activation by mechanical forces. In the second part, we will focus on the recent findings concerning the role of Piezos in mechanical nociception. In the final part, we will discuss the 3D structure of SAKs and will derive a novel hypothesis concerning their gating mechanism. Such a mechanism may be relevant to other types of SACs, including Piezos.

Section snippets

Mechanotransduction: lessons from microbes and invertebrates

SACs are conserved during evolution and are already present in microbes, yeast and plants [6]. For instance, osmotic down-shock opens bacterial SACs, such as the large-conductance mechanosensitive channel (MscL), allowing osmolyte efflux, relieving pressure and preventing cell lysis [14]. Previous studies performed on MscL have provided strong evidence that its conformation is directly dependent on tension in the lipid bilayer 6, 15, 16, 17, 18 (Figure 1a and Box 1).

Pioneering work by Chalfie

The sense of touch in mammals

Activation of mechanosensitive nerve endings, which branch from the dorsal root ganglia (DRG) or trigeminal ganglia (TG) into the skin, transduces mechanical stimuli into action potentials which mediate the sense of touch 1, 2, 7. Touch receptors are diverse and functionally characterized by different pressure thresholds with variable adaptation kinetics (decay of the current in response to a steady mechanical stimulation). Their activation allows the detection and the coding of different types

Piezo1 and Piezo2 are essential components of distinct SACs in mammalian cells

The Neuro2A (N2A) neuronal cell line is characterized by a relatively high-amplitude non-selective current induced by mechanical indentation (200 pA at –80 mV) [10]. All of the transmembrane (TM) proteins with at least two TM domains that are enriched in N2A cells were recently identified using a microarray strategy [10]. By systematically knocking down each of these candidate genes with short interfering RNAs (siRNAs), and mechanically probing N2A cells in the whole cell patch clamp

Are Piezos pore-forming subunits of SACs?

Although mouse Piezo1 (mPiezo1) is reversibly inhibited from the extracellular side by ruthenium red, dPiezo is resistant at a concentration of 30 μM 43, 44. Moreover, at the single-channel level, the conductance of mPiezo1 is about 30 pS, wheras dPiezo conductance is about 10-fold lower [37]. dPiezo shows kinetics comparable to mPiezo2 (Figure 2d). These findings indicate that mPiezo1 and dPiezo clearly underlie two types of SACs with different pharmacological and biophysical properties.

Because

dPiezo and mechanical nociception

Because it is an absolute requirement for the molecular identification of a SAC to show that this candidate is physiologically active in a native environment, new data describing Piezo function in Drosophila are especially important [44]. dPiezo is widely expressed in every sensory neuron, including type I ciliated sensory neurons (campaniform sensillar, thoracic bristles and chordotonal neurons) and type II multidendritic neurons (Figure 3b). Moreover dPiezo is also found in several

Hyperpolarizing SAKs

How Piezos work at the molecular level is still not understood. Therefore, knowledge derived from other better-understood mechanosensing proteins is informative. Recently, the 3D structure of K2P channels (including the SAK TRAAK) has been unraveled, thus providing valuable information about their gating mechanisms 12, 13 (Figure 4). In addition to depolarizing non-selective SACs, the SAKs [TRAAK and TREK-1 (TWIK-related K+ channel)] are also expressed in sensory DRG neurons 52, 53. K2P

Concluding remarks

In conclusion, these recent findings are remarkable breakthroughs in the understanding of molecular mechanotransduction. However, the molecular and functional studies performed with both native and cloned SACs/SAKs still leave us with real difficulties in understanding how they open in response to stretch. More work is clearly needed to identify the specific permeation and gating mechanisms of these channels (Box 2 and 57, 58).

Acknowledgments

We are grateful to Drs Amanda Patel, Bertrand Coste and Ardem Patapoutian for critical reading of this manuscript. We thank Dominique Douguet for help with analysis and illustration of the 3D structural model of the TRAAK K2P channel. B.N. was supported by a grant from the KU Leuven (EUM-PATE07). E.H. thanks the Agence Nationale de la Recherche (ANR) 2008 du Gène à la Physiopathologie, the ANR Physiologie, Physiopathologie, Santé Publique 2011, the Fondation de la Recherche Médicale, the

Glossary

ASH neurons
a pair of ciliated sensory neurons in the head region of C. elegans that are required for nociception, nose touch mechanoreception, chemical avoidance and social feeding.
DEG/ENaC
degenerin/epithelial Na+ channel family. MEC-4/MEC-10 (the mec genes are designated for their ‘mechanosensory abnormal’ phenotype) form a mechanosensory DEG/ENaC channel complex expressed in C. elegans mechanoreceptors. DEG1 and DEGT1 are members of the degenerin family in C. elegans. ASICs are mammalian

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