“Reach out and touch someone.” Some may remember that old TV commercial. Bell Telephone appealed to the human need for communication to grow its business, implying that a phone call was the next best thing to a hug or handshake. At a scale five orders of magnitude smaller, cells also like to reach out and touch their neighbors. They respond not with ears and fingers, but with channels that open on contact, making intercellular communication come alive.

In a previous article about active transport and selectivity filters, we marveled at the precision alignment of amino acid residues in the CFTR channel that employ electrostatic forces to authenticate chloride ions passing through a narrow “selectivity filter” required for entry. CFTR channels remain open all the time for their chloride ion customers. Others require a touch, like the push of a button on a vending machine, to activate. 

A Biological Piezoelectric Effect

One such channel has an interesting name, Piezo2, reminiscent of the piezoelectric effect in physics where applying mechanical stress to certain materials generates electricity. You may have seen a demonstration of this effect when a physics teacher hit a quartz rock with a hammer and generated sparks. In a related way but with different physics, Piezo channels are touch sensitive, and indeed are crucial for our sense of touch.

We have numerous Piezo1 channels in our skin, which respond on contact by opening to let Ca²⁺ ions flood into the cell, triggering neural signals interpreted by the brain as touch. Piezo2-deficiency syndrome, caused by mutations in the PIEZO2 gene, manifests as decreased touch sensation and proprioception, leading to difficulty walking and loss of coordination. The Piezo2 channel has a curious shape, with a dome of three curved arms that look like propeller blades.

News from the Max Delbrück Center adds a partner to Piezo2. 

Every hug, every handshake, every dexterous act engages and requires touch perception. Therefore, it is essential to understand the molecular basis of touch. “Until now, we had known that the ion channel — Piezo2 — is required for touch perception, but it was clear that this protein alone cannot explain the entirety of touch sensation,” says Professor Gary Lewin, head of the Molecular Physiology of Somatic Sensation Lab at the Max Delbrück Center.

For over 20 years Lewin has been studying the molecular basis of the sensation of touch. He and his team have now discovered a new ion channel, named Elkin1, that plays a vital role in touch perception. This is only the second ion channel implicated in the touch perception. [Emphasis added.]

Like other ion channels, Elkin1 is anything but simple. It contains 7 transmembrane proteins with a well-defined structure and selectivity filter. Lewin’s team, who published their findings in Science, first noticed that mice without functional Elkin1 often had reduced touch sensitivity. Then they checked to see if the two mechanically activated (MA) channels cooperated. Strangely, they did not — at least directly. Elkin1, instead, interacts with StomL3, a modulator of Piezo2 sensitivity. Further tests revealed a cooperative role in these three proteins that permits response to low-threshold mechanoreceptors (LTMRs).

Our data support a model in which ELKIN1 and PIEZO2 channels share roles in sensory mechanotransduction in LTMRs and in which both channels can be modulated by STOML3. There is evidence that STOML3 can also modulate MA currents in nociceptors, which is consistent with a role for ELKIN1 in conferring robustness to the C-fiber responses to force. The identification of ELKIN1 as a mechanically gated ion channel necessary for somatosensory function increases our understanding of the entirety of touch transduction.

Cooperation between these three actors gives an animal a wide range of touch sensitivity, from a quick light touch to constant pressure at the point of pain. The take-home lesson is that the sense of touch now looks more complex and more finely tuned than thought. One mechanoreceptor is not enough for exquisite responses to touch, whether it be a hug, handshake, or dexterous act.

Touch-Sensitive Tissue Repairmen

An open access paper by a team from Yale in Science Advances tells about another discovery in mechanosensation. Macrophages, part of the immune system, reside in the extracellular matrix of many tissues. When they sense a disturbance in the force, they slither about like amoebas to the site of repair. Having DNA credentials, they can also signal the nucleus to send reinforcements.

Tissue-resident macrophages play important roles in tissue homeostasis and repair. However, how macrophages monitor and maintain tissue integrity is not well understood. The extracellular matrix (ECM) is a key structural and organizational component of all tissues. Here, we find that macrophages sense the mechanical properties of the ECM to regulate a specific tissue repair program. We show that macrophage mechanosensing is mediated by cytoskeletal remodeling and can be performed in three-dimensional environments through a noncanonical, integrin-independent mechanism analogous to amoeboid migration.We find that these cytoskeletal dynamics also integrate biochemical signaling by colony-stimulating factor 1 and ultimately regulate chromatin accessibility to control the mechanosensitive gene expression program. This study identifies an “amoeboid” mode of ECM mechanosensing through which macrophages may regulate tissue repair and fibrosis.

Lysosomes: Organelles with Mechanosensitive Channels

Not all mechanosensitive channels reside on the external lipid membranes of cells. Here’s one on the membrane of an important organelle: the lysosome. Li et al., publishing in Nature (open access), explored a protein named TMEM63 that works in a mechanosensitive channel on the membranes of lysosomes. Erika Reiderer and Dejian Ren, commenting on this paper in the same Nature issue, describe the lysosome as “a vital organelle with an acidic pH that digests and recycles cellular materials thanks to more than 50 digestive enzymes and many transporters.” Now, one of those parts turns out to be an intercellular mechanosensitive ion channel.

Because lysosomes are embedded in signaling networks with other organelles, it makes sense that they often feel the need to reach out and touch someone. The busy interior of a cell makes contacts unavoidable and frequent. A figure in the commentary shows mechanical stimuli impinging on the lysosome’s membrane in various ways. The TMEM3 channels interact with signals from other organelles such as mitochondria, peroxisomes, the endoplasmic reticulum (ER) via their tethering proteins, effectors and transporters; microtubules being carried by motor proteins; endosomes coming in from the exterior; nutrient sensors via the mTORC1 pathway; and possibly mechanical signals from the V-ATP rotary motors embedded in the lysosomal membrane. (V-ATPases, by the way, rotate similarly to ATP synthase, but hydrolyze ATP for protons to acidify the interior of the lysosome.) A politician could hardly shake more hands than these contact-sensitive TMEM63 channels do constantly!

Li’s team was able to measure electrical currents in these TMEM63 channels, which is truly remarkable, given that they were measuring conductance on the membranes of tiny organelles in response to mechanical forces inside the cells of fruit flies! They even measured the pressure that triggered the responses. What amazing times we live in, where such measurements are possible, and we can image the molecular machines themselves. The team also investigated comparable channels named TMEM63A in mice, one of three mammalian counterparts found in our bodies, too. No mention was made of evolution, other than to note that all these homologues are “evolutionarily conserved” — i.e., unevolved.

Reiderer and Ren consider this a groundbreaking discovery ripe for more research. 

The Li et al. study opens a new frontier in lysosomal physiology. As with many other groundbreaking discoveries, it also prompts more questions than answers. How is lysosomal TMEM63 opened by mechanical force? Does it functionally or physically interact with other, better-known lysosomal channels to coordinate lysosomal physiology and cellular signalling? How does a mechanosensing channel regulate a lysosomal function as basic as substrate digestion? Is the channel also regulated by organelle membrane lipids and extracellular cues, such as nutrients and growth factors? Finally, the mechanisms for sensing mechanical forceby plasma membranes are — somewhat annoyingly to physiologists — highly diverse between cells and across species. Are the mechanisms used by lysosomes more uniform? With the newly found role of TMEM63, it is hoped that these questions can be answered shortly.

Answers will come from engineers specializing in biophysics. It’s the kind of research favorable to ID, where scientists investigate a phenomenon on the assumption that if something exists and is working, it has a purpose.