CHAPTER THREE

Contribution of Mechanosensitive Ion Channels to Somatosensation Reza Sharif-Naeini1 Department of Physiology and Cell Information Systems Group, McGill University, Montreal, Quebec, Canada 1 Corresponding author: e-mail address: [email protected]

Contents 1. The Evolution of Mechanosensing 2. MSCs in Nociceptors 3. Difficulties in Identifying Genes Encoding MSCs 3.1 Piezo2 as a mechanosensitive channel in sensory neurons 4. Gating Mechanisms of MSCs 5. Role of MSCs in the Transmission of Noxious Mechanical Inputs 6. Sensitization of MSCs Is Necessary for the Induction of Mechanical Allodynia 7. Potassium-Selective MSCs in Nociceptors References

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Abstract Mechanotransduction, the conversion of a mechanical stimulus into an electrical signal, is a central mechanism to several physiological functions in mammals. It relies on the function of mechanosensitive ion channels (MSCs). Although the first single-channel recording from MSCs dates back to 30 years ago, the identity of the genes encoding MSCs has remained largely elusive. Because these channels have an important role in the development of mechanical hypersensitivity, a better understanding of their function may lead to the identification of selective inhibitors and generate novel therapeutic pathways in the treatment of chronic pain. Here, I will describe our current understanding of the role MSCs may play in somatosensation and the potential candidate genes proposed to encode them.

We can sense mechanical changes in our outer environment, such as touch and sounds, and in our inner environment, such as fluid flow and osmotic shifts, because these stimuli are detected by sensory cells and converted into electrical signals. This conversion occurs in less than a millisecond and is therefore thought to involve mechanosensitive ion channels (MSCs) rather than engage second messenger intermediates.1–3 Interestingly, these MSCs

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Hearing

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Figure 1 Evolution of MSCs across species. Schematic diagram of the expression of MSCs in different kingdoms, along with the proposed function of the MSCs in each of these kingdoms.

exist in a wide variety of organisms and must have therefore been present in the early stages of life on the planet. Indeed, mechanotransduction is one of the earliest functions developed by living organisms, appearing billions of years ago. While the function of MSCs remained simple in the early life forms, it became more and more complex through evolution. In mammals, these channels are expressed in several tissues and are involved in a multitude of essential physiological functions (Fig. 1). In the next sections, I will review several aspects of MSCs, ranging from their evolution, gating mechanisms, role in cell excitability, and tissue distribution. This review will emphasize the role these channels play in the transmission of painful mechanical stimuli in sensory neurons during physiological and pathological conditions.

1. THE EVOLUTION OF MECHANOSENSING Mechanosensing dates back about 3.8 billion years, when microbes one of the first forms of life appeared on the planet.4 In these cells, the primary function of MSCs is to act as emergency valves releasing excess

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osmolytes when their extracellular environment became hypoosmotic, such as during rainfall.5 As evolution progressed, these channels remained expressed in higher organisms (Fig. 1), such as plants, where their roles have been associated with root gravity sensing,6 as well as the thigmotropic7 and thigmonastic8 behaviors of the vine and the flytrap, respectively. In mammals, these channels attained their greatest functional diversity and underlie several essential physiological functions. In kidney epithelial cells, MSCs protect against mechanical stresses such as compression caused by cyst growth.9 In vascular smooth muscle cells, MSCs act as sensors of membrane tension and trigger the myogenic tone of resistance arteries.10–12 In endothelial cells, they can sense blood flow and can stimulate arterial vasodilation.13,14 These channels are expressed in the nerve terminals of nodose ganglia neurons, located in the wall of the aortic branch, where they sense blood pressure and can trigger the baroreflex.15–17 In the supraoptic nucleus of the hypothalamus, these channels are responsible for the intrinsic osmosensitivity of vasopressin neurons18,19 and trigger the release of the antidiuretic hormone to induce water reabsorption. In hair cells of the inner ear, these channels are responsible for the detection of movement in the cilia, responsible for our capacity to detect sounds.20–22 Finally in the nerve terminals of our sensory neurons, located in the skin and other organs, these channels underlie our capacity to detect mechanical stimuli such as touch and pain.23–28

2. MSCs IN NOCICEPTORS The ability of neurons to detect and transduce mechanical stimuli impinging on them is a fundamental process that underlies hearing, balance, touch, and pain.20,25,29 It is generally accepted that this sensitivity is conferred by the presence of MSCs on the plasma membrane of these neurons.20,24,25 An increase in the sensitivity of MSCs, or in their expression at the plasma membrane, may therefore result in enhanced mechanosensation. Remarkably, although mechanical hypersensitivity in nociceptors is a cause of chronic inflammatory pain, including in rheumatoid arthritis and osteoarthritis,30–32 the role of MSCs in these pathologies has not been examined. This is due in part to our lack of knowledge of the properties of MSCs in nociceptors, and how the function of these channels can be modulated by accessory proteins. Advances in our understanding of MSCs come from electrophysiological studies performed in vitro on isolated sensory neurons. All these experiments

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have been done by recording mechanically activated (MA) whole-cell or single-channel currents at the cell soma of isolated neurons. Given the inaccessibility of nociceptor peripheral terminals, somatic recording from isolated nociceptors is the only approach currently available to study MSCs.24,26–28,33–57 Somatic recording is a standard approach in molecular pain research because the membrane of the cell body expresses all the molecules that determine the function of these neurons.58–62 The clearest demonstration that receptors in the nerve terminals are also expressed in the cell body is that capsaicin, which selectively activates the transient receptor potential, vanilloid-1 (TRPV1)-containing nociceptors when injected in the skin,63 can selectively activate nociceptors when applied to their soma in in vitro experiments.63–74 Furthermore, inflammatory conditions associated with increased TRPV1 responses in peripheral terminals are also associated with an increased responsiveness at the cell body.75,76 If the same distribution occurs for MSCs in nociceptors, we would expect that the somatically recorded currents elicited by mechanical stimulation of the nociceptor neurites or soma would be similar. Indeed, it has been reported that mechanical stimulation of nociceptors’ soma or distant neurites over 70 μm away produces comparable inward currents.23 This indicates that mechanisms that activate MSCs in distant neurites are the same as those in the soma. These experiments have helped identify important characteristics of MSCs in nociceptors. Whole-cell voltage-clamp recordings from nociceptors indicate that these neurons display a MA slowly adapting (SA) current.38,40,41,55,77 In current-clamp experiments, these neurons fire tonically in response to a mechanical stimulation, irrespective of the stimulus velocity or duration.41 This slow adaptation kinetics might be a critical aspect of nociceptive signal generation41 that ensures that the pain signal gets transmitted to the spinal cord and brain. Consequently, if the adaptation kinetics of the SA current was slower, or removed, one might expect that these nociceptors might fire more action potentials and generate a longer lasting pain signal. The adaptation in these neurons is likely an intrinsic feature of the MSCs because electrophysiological experiments have demonstrated that the adaptation is almost completely removed when the recording is performed at positive membrane potentials.34 Moreover, whether the adaptation kinetics is modified in the setting of chronic pain remains to be determined. In single-channel recordings from nociceptors, it was demonstrated that these neurons express a 14-picoSiemens, highthreshold mechanosensitive channel24,26,27,53 that is voltage-independent and has a reversal potential near zero mV, consistent with a nonselective

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cation channel.26,27 This channel has been speculated to be responsible for the mechanically induced SA current in nociceptors,40,41 but experimental evidence is lacking. Finally, pharmacological characterization indicates that the SA current is blocked by the trivalent ion gadolinium, the inorganic dye ruthenium red, and by a novel conopeptide named NMB-1.24,26,27,53 Despite these observations, advances in our understanding of MSC function in nociceptors have been slow primarily because the genes encoding these channels or their modulators are unknown. Indeed, genetic studies have implicated genes necessary for the mechanosensory function of invertebrate nociceptors, notably osm9 in the nematode and Painless and Dmpiezo in Drosophila larvae,36,78,79 yet no valid candidate genes encoding a nonselective cationic MSCs or MSC modulators in mammalian nociceptors have emerged.

3. DIFFICULTIES IN IDENTIFYING GENES ENCODING MSCs The identification of candidate proteins forming an MSC is difficult for several reasons. First and foremost, most, if not all, cells known to date express an MSC. This renders a functional cloning approach such as the one used to identify the capsaicin receptor almost impossible. Second, purification from mechanosensitive cells is difficult because MSCs are not expressed in large amounts. For instance, each hair cell is thought to have about 50–100 transduction channels.80–82 A similar number is also believed to be present on osmosensitive vasopressin neurons. Third, establishing that a candidate protein is intrinsically mechanosensitive is a difficult task because it has to be expressed in heterologous systems, which already have their own set of MSCs. One would therefore have to look at an increase in mechanically evoked current above the endogenous level. This can be bypassed by a labor-intensive protein purification and reconstitution in artificial lipids, devoid of any other protein that may interfere with the recording. Nonetheless, the chances of success remain low because this approach still makes the assumption that eukaryotic MSCs are made of homomeric subunits, whereas in reality, the MSC may be a mechanotransduction complex requiring several accessory subunits, including specialized elements of the cytoskeleton and the extracellular matrix, as is the case for the MSC of the nematode Caenorhabditis elegans.3,83,84 Because of these difficulties, very few candidate proteins have been identified as MSCs. In Escherichia coli, the genes encoding the MSCs were identified some 20 years ago and have since

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been extensively studied.85 But they have no eukaryotic homologs. In mammals, until 5 years ago, the only known bona fide MSC was the potassiumselective (hyperpolarizing) MSC named TREK-1 (also known as KCNK2),86,87 a member of the two-pore potassium (K2P) channel family. More recently, two novel genes, named Fam38A and Fam38B, encoding depolarizing cationic MSCs Piezo1 and Piezo2 were identified.34–37

3.1. Piezo2 as a mechanosensitive channel in sensory neurons A significant advancement in the field of mechanotransduction came with the identification of Piezo1 and Piezo2 by the Patapoutian lab in 2010. In the mouse, Piezo1 is a 30-transmembrane domain protein expressed primarily in the lung, bladder, skin, colon, and kidney. Piezo2, on the other hand, is a 34-transmembrane domain protein that is highly expressed in dorsal root ganglia, lung, and bladder. Such high expression level of Piezo2 in sensory neurons made it an exciting candidate as the mechanosensor in nociceptors. Using in situ hybridization combined with immunohistochemistry, Coste and colleagues demonstrated that Piezo2 mRNA is expressed in a subset of peripherin (60%)- and neurofilament 200 (28%)-immunopositive neurons, typically associated with large diameter, touch-sensitive Aβ neurons. Additionally, Piezo2 was also expressed in TRPV1-immunoreactive neurons, which are nociceptors. These observations lead the authors to speculate that Piezo2 was likely involved in the sensation of noxious mechanical stimuli. Although the Drosophila melanogaster homolog of Piezo, which shares only 24% homology with the mouse piezo genes, was shown to be involved in mechanosensory nociception, the involvement of Piezo2 in mammalian somatosensation seems to be restricted to the detection of touch stimuli. Indeed, knocking down Piezo2 in cultured mouse sensory neurons did not affect the slow-adapting MA current, found in nociceptors,25,38,77 but only reduced the rapid adapting MA current, found in touch-sensitive fibers.55,88 This is also supported by experiments demonstrating that the zebrafish homolog of piezo2, which shares 63% sequence homology, is specifically expressed in a subset of neurons responsible for detecting light touch, and its knockdown leads to deficits in the response to light touch without affecting the responses to noxious chemical or mechanical stimuli.89 The role of Piezo2 in the mammalian sense of touch is further supported by its expression in Merkel cells, the gentle touch receptor in the skin that enables us to distinguish the fine details of objects.90–94 Indeed, a recent

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report by Woo and colleagues demonstrated that the intrinsic mechanosensitivity of Merkel cells is due to the expression of Piezo2.92,95 Deletion of this gene in Merkel cells abolishes their mechanosensitivity and the mice behavioral response to gentle touch becomes impaired.95 The identity of the mammalian mechanosensitive channel of nociceptor therefore remains elusive.

4. GATING MECHANISMS OF MSCs MSCs are embedded in a lipid bilayer where they are sensitive to local, as well as global, stress in the bilayer. When a mechanical stimulus impinges on a cell’s membrane, the stress is distributed to all components including the bilayer, the cytoskeleton (CSK), and the extracellular matrix (ECM), which converge on the MSC and induce a transition from the closed to open state. How the convergence of this stress induces the transition has been debated over the years and has led to two possible mechanisms: the bilayer model and the tether model96 (Fig. 2). Most of what we know about the bilayer model comes from studies of the bacterial MSCs.29 In this model, the stresses

Bilayer model

Tether model ECM

Tension

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Figure 2 Models of the gating of MSCs. Two of the most popular models of MSC gating by mechanical stimuli. In the bilayer model (left panel), an increase in membrane tension is believed to cause a thinning of the plasma membrane, thus exposing hydrophobic residues of the channels that were previously embedded in the bilayer. This forces the channel subunits to tilt and induces an opening. In the tether model (model to the right), the membrane stress is conveyed to the channel by means of accessory proteins, such as the cytoskeleton or the extracellular matrix. These are thought to directly interact with the channel subunit.

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absorbed by membrane (or cytoskeleton or ECM) cause an increase in the tension in the bilayer, which modifies the interaction between the hydrophobic portion of the protein and the lipid bilayer and causes the protein to change its configuration and tilt its membrane helices, inducing its opening.97,98 This gating mechanism is supported by experimental data obtained in artificial bilayer experiments. In the tether model, the stresses absorbed by the membrane are transmitted to the channel via the interaction with ECM or CSK elements.29 These additional structures are therefore essential components of the transduction machinery. This model was first proposed for hair cell transduction96 but has since been observed in other systems including osmosensory neurons99–101 and pain-sensing neurons.27 In hair cells, the transduction channel is tethered to an external tip link that connects the stereocilia to the actin cytoskeleton. Bending of this stereocilia stretches the channel and causes its opening.96 Loss of tip links can effectively abolish transduction.102 In vasopressin neurons of the hypothalamus, osmosensing relies on a stretch-inactivated ion channel that is linked to the actin and tubulin cytoskeleton.99,101 Disrupting either filaments with depolymerization agents can blunt osmosensory transduction, whereas increasing filament density with stabilizing agents increases the coupling between mechanical stresses and channel opening, i.e., increases the sensitivity of the system. Finally, depolymerization of either microtubules or F-actin reduced the sensitivity of MSCs in touch- and pain-sensing neurons.26,27 Because of the importance of the integrity of the ECM or the CSK in the tethered model, any signaling pathway that converges on these elements has the potential to modulate the sensitivity of the mechanotransduction apparatus. Examples of these mechanisms have been proposed to underlie the effect of angiotensin on the osmosensitivity of vasopressin neurons.100

5. ROLE OF MSCs IN THE TRANSMISSION OF NOXIOUS MECHANICAL INPUTS The neuronal processes leading to the sensation of pain can be divided into four distinct steps: transduction, conduction, processing, and interpretation (Fig. 3). The first step is the transduction of the mechanical stimulus into an electric signal. The activation of the MSCs in the terminals of the nociceptive afferents by a noxious stimulus generates a membrane depolarization termed receptor potential. Mechanosensitive channels in touchsensitive neurons have a low threshold for activation by mechanical stimuli

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Figure 3 Schematic diagram of the transmission of painful mechanical information from the periphery to the brain. The mechanical stimulus is first detected by the MSCs (step 1), which transforms the mechanical energy into an electrical signal. The conduction (step 2) of the signal is enabled by the presence voltage-gated sodium channels, which carry the electrical input to the spinal cord for its processing (step 3). There, the signal is processed before it is transmitted to projection neurons, which carry the information to supraspinal centers (step 4).

whereas those expressed in nociceptors have a high threshold.27 If this wave of depolarization is large enough when it reaches the spike trigger zone, a region enriched in voltage-gated sodium channels, then an action potential is generated and conducted (step 2) along the sensory nerve toward the spinal cord. The third step occurs in the spinal cord, where the signal is processed by interneurons or directly transmitted to projection neurons. The latter will transmit the signal to the brain (step 4), where it is interpreted as painful. During chronic pain conditions associated with a mechanical sensitization of nociceptors, such as in rheumatoid arthritis or osteoarthritis, the pathology underlying the hypersensitivity can be in all four steps.30,32

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Indeed, the release of inflammatory cytokines in the joint is likely the primary cause of nociceptor sensitization.103,104 Although the downstream target of these cytokines is unknown, it has been shown that blocking the NaV1.8 subset of sodium channel in the setting of OA can attenuate both the hyperexcitability of nociceptors and the behavioral pain symptoms in a preclinical OA model.105 The processing of sensory information in the dorsal horn of the spinal cord can also be affected, as shown in rodent models of OA, where microglia and astrocytes show significant hyperactivity in the later stages of the disease.106 Finally, changes at supraspinal sites can take place (step 4). In a surgical model of OA, an increased functional connectivity of supraspinal neuronal networks was observed in the nucleus accumbens and ventral posterior lateral thalamus.107 Furthermore, when compared to controls, patients with chronic pain due to hip osteoarthritis had a characteristic decrease in gray matter in the regions of the anterior cingulate cortex (ACC), right insular cortex and operculum, dorsolateral prefrontal cortex (DLPFC), amygdala, and brainstem.108 Of those that became pain-free following hip surgery, the gray matter size increased in the DLPFC, ACC, amygdala, and brainstem.108 This suggests that supraspinal changes take place in the setting of OA pain, though the mechanisms are currently elusive. The remainder of this review will focus on the peripheral mechanisms underlying the sensitization of nociceptors that produces mechanical allodynia. Recent therapeutic approaches have targeted the transmission of the mechanical stimulus to the spinal cord (step 2) through the development of selective blockers of voltage-gated sodium channels.109–111 An alternative approach could be to identify the MSCs responsible for the transduction of the noxious mechanical stimulus, thus blocking the activation of the nociceptor. In healthy individuals, the role of MSCs in nociceptors is to warn the organism about any potential harmful mechanical stimuli. However, during chronic inflammatory pain, nociceptors become sensitized to mechanical stimuli30,31,112 and become activated by innocuous, touch-like, stimuli, a phenomenon that underlies part of the mechanical allodynia seen in these conditions.

6. SENSITIZATION OF MSCs IS NECESSARY FOR THE INDUCTION OF MECHANICAL ALLODYNIA During inflammation, proinflammatory mediators sensitize the nerve terminals of nociceptors to mechanical stimuli,30 causing these afferents to become activated by innocuous stimuli. This increased excitability can be

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due to changes in the function of voltage-gated ion channels or of the mechanotransduction apparatus in the nerve terminals.52 A decrease in expression of background potassium channels, responsible for maintaining the resting membrane potential at a hyperpolarized level, could cause a slight membrane depolarization,113–115 thus helping a mechanically induced depolarizing wave to reach the action potential threshold (APT; Fig. 4). By itself, this mechanism would enhance the excitation of the nociceptor only if a mechanically applied stimulus is of high enough (noxious) intensity, Naive A

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Figure 4 Proposed contribution of MSCs to the development of mechanical allodynia. The activation of MSCs in nociceptors can only be done by high-intensity stimuli. During inflammation, both hyperalgesia and allodynia are visible. However, without the sensitization of MSCs, it will be impossible to generate mechanical allodynia. (A) A decrease in background potassium conductances will depolarize the plasma membrane and facilitate the generation of an action potential by mechanically evoked depolarization. (B) A decrease in the action potential threshold would also facilitate the generation of an action potential. However, in both situations (top two rows), the precipitation of mechanical allodynia would not be possible without the sensitization of MSCs (lower panel). It is expected that only if the activation threshold of the MSC is reduced (C), there will be a receptor potential generated that can elicit an action potential. This sensitization would explain mechanical allodynia.

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producing a hyperalgesia-like state. Alternatively, increased expression of NaV1.9 channels,113,116–118 which have a hyperpolarized activation threshold,119,120 would lower the APT and facilitate firing in nociceptors (Fig. 4B). Once again, this enhancement of the firing can occur only if the mechanical stimulus can open the MSC, otherwise the depolarization will not occur. A sensitization of the MSCs, on the other hand, will lead A P

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Figure 5 Example of sensitization of MSCs during inflammation. Illustration of the behavior of MSCs in nociceptors from naïve or inflamed animals. (A) The activation threshold of MSCs is typically high under normal conditions ( 60 mm Hg in the example). The downward deflections represent openings of single MSCs in response to increased tension produced by steps of negative pressure pulses through the recording electrode. During inflammatory pain, MSCs can open at lower thresholds through mechanisms that have yet to be determined. (B) Three different scenarios can take place during the sensitization of MSCs. Their maximum activity can remain the same, indicating that there is no upregulation in the number of channels, but those present on the membrane now open at lower mechanical stimuli, predisposing the system for mechanical allodynia (left panel). There may be an increased expression of the MSCs, without altering their activation threshold, thus enabling the development of mechanical hyperalgesia (middle panel). Finally, a combination of both mechanisms can occur, which would generate both allodynia and hyperalgesia (right panel).

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to the generation of a receptor potential with low-intensity stimuli and will be able to elicit mechanical allodynia (Fig. 4C). Although these three mechanisms are described individually here, they are likely to occur at the same time to produce both mechanical allodynia and hyperalgesia during inflammation (Fig. 5).

7. POTASSIUM-SELECTIVE MSCs IN NOCICEPTORS Another level of complexity is added to the role of MSCs in nociceptors by the presence of potassium-selective MSCs on the same terminals.121,122 Activation of the latter leads to membrane hyperpolarization and prevents the cell from firing action potentials. This means that when a mechanical stimulus impinges on the nerve terminal of a nociceptor, it will activate the depolarizing, nonselective cationic MSC, as well as activate the hyperpolarizing, potassium-selective MSC. The perception of pain at supraspinal sites would therefore indicate that the level of depolarizing exceeded the level of hyperpolarizing. However, conditions with decreased expression of Kv1.1 or K2Ps would therefore lead to a mechanical hypersensitivity. Evidence for this has been previously reported, whereby mice with a gene deletion for TREK-1 have significantly lower mechanosensitivity.122 In summary, several candidates have been proposed to form the MSC in nociceptors, but definite proof is lacking. Physiological studies in animal models of inflammatory pain have provided hints that the activity of MSCs in nociceptors might be impaired. However, no report has clearly examined, at the single-channel level, how the properties of these channels would be affected in conditions such as rheumatoid arthritis or osteoarthritis. Further studies will be required to answer these questions.

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Contribution of mechanosensitive ion channels to somatosensation.

Mechanotransduction, the conversion of a mechanical stimulus into an electrical signal, is a central mechanism to several physiological functions in m...
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