Nobel Prize in Physiology or Medicine 2021

Electrophiles activate the transient receptor potential ion channel TRPA1 by a two-step cysteine modification mechanism, which stabilizes a cytoplasmic loop that controls gating and calcium permeability.

Cryo-electron microscopy has undergone a resolution revolution—here, this method has been combined with lipid nanodisc technology to solve structures of TRPV1, the receptor for capsaicin, in a membrane bilayer, revealing mechanisms of lipid and ligand regulation.

The high-resolution electron cryo-microscopy structure of the full-length human TRPA1 ion channel is presented; the structure reveals a unique ankyrin repeat domain arrangement, a tetrameric coiled-coil in the centre of the channel that acts as a binding site for inositol hexakisphosphate, an outer poor domain with two pore helices, and a new drug binding site, findings that collectively provide mechanistic insight into TRPA1 regulation.

Using a peptide toxin and small vanilloid agonists as pharmacological probes, high-resolution electron cryo-microscopy structures of rat TRPV1–ligand complexes are solved; these structures highlight conformational differences between TRP and voltage-gated ion channels in their active states, and suggest a dual gating mechanism that may account for the ability of members of the TRP channel superfamily to integrate diverse physiological signals.

A high-resolution electron cryo-microscopy structure of the rat transient receptor potential (TRP) channel TRPV1 in its ‘closed’ state is presented; the overall structure of this ion channel is found to share some common features with voltage-gated ion channels, although several unique, TRP-specific features are also characterized.

Nitric oxide can be produced by nitric oxide synthase or by nitrite reduction, but whether the latter occurs inside cells is unknown. Here, the TRPV3 ion channel is shown to induce nitrite-dependent nitric oxide production in keratinocytes, where it has a role in thermosensory behaviour and wound healing.

TRPV1 is a member of the family of temperature-activated transient receptor potential ion channels. This study identifies mutations in the outer pore region of TRPV1 that impair temperature activation by ablating long channel openings.

Snakes are notoriously apt at generating 'thermal images' of predators or prey. The underlying physiology has been unclear, although in snakes such as pythons, vipers and boas, infrared signals are initially received by the pit organ. Here it is shown that pit-bearing snakes rely on heat detection by the ion channel TRPA1. This extends the sensory repertoire of the TRPA1 family of proteins, which detect chemical irritants in mammals and thermal variations in insects.

Although certain ion channels can be gated by temperature, it is currently unknown how this occurs. Here, the authors identify regions of TRPV3 that are critical for heat sensation, yet independent of other channel gating mechanisms.

The identity of the transduction molecules underlying cold sensation has long been a mystery in sensory physiology. Now, using a combination of electrophysiological recording, calcium imaging and behavioural analysis, TRPM8 is shown to have a major role in normal cold transduction in mice.

Large transmembrane proteins of the Piezo family assemble as tetramers to form a new class of ion channel that can be activated by mechanical force.

The Drosophila Piezo protein is shown to function in sensory neurons to transduce mechanical force in vivo.

PIEZO2 is expressed in the bladder urothelium and sensory neurons innervating the lower urinary tract and is a key mechanosensor for the control of urination.

The cryo-electron microscopy structure of full-length mouse Piezo1 reveals six Piezo repeats, and 26 transmembrane helices per protomer, and shows that a kinked helical beam and anchor domain link the Piezo repeats to the pore and control gating allosterically.

The mechanoreceptor Piezo2 is required for both the Hering–Breuer inflation reflex in adult mice and the inflation of the lungs of newborn mice.

Auditory hair cells contain mechanotransduction channels that are activated by sound. The authors show that Piezo2, a mechanotransduction channel important for touch perception, is expressed in auditory hair cells. Surprisingly, Piezo2 is not the mechanotransduction channel essential for auditory perception and is instead observed after damage to hair cells.

Proprioception, the sense of body and limb position, begins in nerve cells called proprioceptors that are activated by muscle or joint stretch. The molecular mechanism of mechanotransduction in mammalian proprioceptors is unknown. The authors show that the mechanically activated cation channel Piezo2 is the principal mechanotransducer in murine proprioceptors.

Lukacs et al. identify mutations in the PIEZO1gene in patients with congenital lymphatic dysplasia. The study also characterizes the functional consequence of the disease-associated Piezo1 mutant proteins and show attenuated ion channel function in cellular context.

Piezo ion channels function as mechanotransducers involved in vascular development and touch sensing, but their structural features remain unknown. Here the authors find that the C-terminal region of Piezo protein encompasses the pore and identify a glutamate residue within this region involved in ion conduction properties.

Mice lacking the mechanically activated ion channel Piezo2 in both sensory neurons and Merkel cells are almost totally incapable of light-touch sensation while other somatosensory functions, such as mechanical nociception, remain intact, implying that other mechanically activated ion channels must now be identified to account for painful touch sensation.

A mouse study shows that non-neuronal epidermal Merkel cells aid fine-touch perception in the skin through their expression of the Piezo2 mechanosensitive cation channel which then actively tunes the response to touch in adjacent somatosensory neurons.

The cellular basis of touch has long been debated, in particular the relationship between sensory neurons and non-neuronal cells; a mouse study uses optogenetics to identify their distinct and collaborative roles, with skin-derived Merkel cells both transducing touch and actively tuning responses of touch-sensitive neurons.

Dehydrated hereditary stomatocytosis is a genetic condition in which the permeability of red blood cells to cations in increased. Albuisson and colleagues find that mutations in the mechanically-activated PIEZO1 ion channel are the major cause of the disease and result in more slowly inactivating currents.

This Review summarizes developments in the field of mechanically activated ion channels, which have been driven by the increasing breadth of structural studies.

This Review discusses recent findings in transient receptor potential (TRP) channel structural biology and the impact of these findings in drug development and clinical indications. It also addresses the challenges of modulating TRP channels and the need for targeted approaches to minimize potential side-effects due to the multifunctional roles of TRP channels.

Mammalian skin contains an array of specialized structures that transform mechanical forces into electrical signals. Handler and Ginty provide a comprehensive overview of the features of the skin’s mechanosensory end organs and the neurons with which they associate and consider how their diverse properties contribute to the sense of touch.

This article discusses the latest advances in the mechanisms of diabetic sensorimotor peripheral neuropathy (DSPN) and painful DSPN, originating both from the periphery and the central nervous system, and outlines the emerging diagnostics and treatments.

Transient receptor potential (TRP) channels are a family of 28 nonselective cationic channels that are heterogeneously expressed in different regions and cell types of the heart. In this Review, the authors summarize the various physiological and pathological cardiac processes in which TRP channels are involved.

Soon after their discovery in 2010, Piezo channels became a paradigm for studying mechanosensitive ion channels. These channels respond to physiologically relevant forces in diverse cellular contexts, and their dysfunction has been linked to various diseases. We are now starting to understand gating mechanisms of Piezo channels and their key roles in physiology.

Transient receptor potential (TRP) channels are the most prominent family of nociceptive ion-channel transducer proteins. This Review highlights evidence supporting particular TRP channels as targets for analgesics, indicates the likely efficacy profiles of TRP-channel-acting compounds and looks at recent clinical trials with TRP-channel-acting drugs.

The electron cryo-microscopy structure of full-length mouse Piezo1 reveals unique topological features such as the repetitive transmembrane helical units that constitute the highly curved transmembrane region, and identifies regions and single residues that are crucial for the mechanical activation of the channel.

The cryo-electron microscopy structure of mouse PIEZO2 is determined and compared to that of PIEZO1, providing insights into the potential gating mechanisms of these mechanosensitive ion channels.

Cryo-electron microscopy and high-speed atomic force microscopy reveal that PIEZO1 can reversibly deform its shape towards a planar structure, which may explain how the PIEZO1 channel is gated in response to mechanical stimulation.

The stomatin domain protein STOML3 is required for the sensation of touch. Here, Poole et al.show that STOML3 enhances the activity of mechanosensitive Piezo1 and Piezo2 ion channels by reducing their activation thresholds, and that it achieves this through its stomatin domain.

A cryo-EM structure of rabbit TRPV2 in a putative desensitized state suggests secondary-structure reorganization in S6 during channel gating.

The X-ray crystal structure of rat transient receptor potential channel TRPV6 at 3.25 Å resolution is reported, providing new insights into its assembly and calcium-selective permeation.

Electron cryo-microscopy structures of mouse TRPM4, a calcium-activated, non-selective cation channel, in the apo and ATP-bound states.

The structure of the Ca²⁺-activated, non-selective ion channel TRPM4 bound to the agonist Ca²⁺ and a modulator decavanadate, solved using electron cryo-microscopy.

Three transient receptor potential channels (TRPA1, TRPV1 and TRPM3) mediate sensitivity to acute noxious heat in mice in a redundant system; mice lacking all three show severe deficits in heat sensing, whereas double-knockout mice do not.

Stem cells of the Drosophila midgut sense mechanical signals in vivo through the stretch-activated ion channel Piezo, which is expressed on previously unidentified enteroendocrine precursor cells.

Piezo1 is a large trimeric ion channel activated by mechanical stimulus. Here the authors identify chemical activators of Piezo1 that utilize a lever-like mechanotransduction pathway for long-range allosteric gating.

PIEZO proteins form mechanosensitive ion channels. Here the authors present electrophysiological measurements that show that PIEZO channels are also modulated by voltage and can switch to a purely voltage gated mode, which is an evolutionary conserved property of this channel family.

Cryo-EM structures of mouse TRPV3 in open, closed and intermediate states, obtained by incubation of the protein samples at different temperatures immediately prior to freezing, offer insight into conformational changes induced by heat in TRPV3.

The TRPV1 ion channel is a heat-sensing receptor that is also activated by vanilloid compounds, but the molecular underpinnings of thermosensing have remained elusive. Here authors use in solution NMR on the isolated human TRPV1 S1-S4 domain and show that this domain undergoes a non-denaturing temperature-dependent transition with a high thermosensitivity.

Menthol in mints elicits a coolness sensation by selective activation of TRPM8 ion channel. Here authors dock menthol to TRPM8 and systematically validate their menthol binding models with thermodynamic mutant cycle analysis in functional tests, and shed light on TRPM8 activation by menthol at the atomic level.

Cryo-EM structures of the heat-activated TRP channel TRPV3 in lipid nanodiscs at different temperatures reveal a conformational wave involved in the gating process.

Multiple cryo-EM structures of rat TRPV1 at different temperatures illustrate steps in the heat-dependent gating of this important sensory receptor.

Cryo-EM structures of zebrafish TRPM5 reveal closed and Ca²⁺-bound open states, a unique Ca²⁺ binding site that modulates voltage sensitivity and the mechanism of antagonist action.

A magnetic torque actuator has been developed and is capable of modulation of neurons expressing the mechanosensitive ion channel, Piezo1, resulting in long-distance control of locomotion of mice.