TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels

Wang, Zheng; Rawson, Shaun; Shen, Zhangfei; Tamilselvan, Elakkiya; Smith, Harper; Halford, Julia; Shen, Chen; Murthy, Swetha E.; Ulbrich, Maximilian H.; Sotomayor, Marcos; Fu, Tian‐Min; Holt, Jeffrey R.

doi:10.1016/j.neuron.2023.07.006

Cited by 32 publications

(20 citation statements)

References 76 publications

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“…It is worth noting that a similar chimera of AtOSCA1.2 with the IL2 domain of the human ortholog TMEM63A (OSCA1.2 63A IL2 ), containing most of the intracellular domain which includes the BLD as well as the dimerization domain, presented little inactivation of SAC akin to monomeric TMEM63A WT 29 . This behavior was not due to an inability of OSCA1.2 63A IL2 to dimerize, as the monomeric OSCA1.2 5Mu , obtained by disrupting the dimer interface with 5 mutations while maintaining OSCA1.2 WT BLD, exhibited pressure-induced SAC gating similar to OSCA1.2 WT 29 . This new evidence, taken together with the decrease in the apparent poking sensitivity of the OSCA1.2 OSCA3.1-BLD chimera in this study, suggests that the BLD plays a role in the force-induced gating of the OSCA family.…”

Section: Discussionmentioning

confidence: 99%

Structure-guided mutagenesis of OSCAs reveals differential activation to mechanical stimuli

Jojoa-Cruz,

Dubin,

Lee

et al. 2023

Preprint

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The dimeric two-pore OSCA/TMEM63 family has recently been identified as mechanically activated ion channels. Previously, based on the unique features of the structure of OSCA1.2, we postulated the potential involvement of several structural elements in sensing membrane tension1. Interestingly, while OSCA1, 2, and 3 clades are activated by membrane stretch in cell- attached patches (i.e., they are stretch-activated channels), they differ in their ability to transduce membrane deformation induced by a blunt probe (poking). In an effort to understand the domains contributing to mechanical signal transduction, we used cryo-electron microscopy to solve the structure ofArabidopsis thaliana(At) OSCA3.1, which, unlike AtOSCA1.2, only produced stretch- but not poke-activated currents in our initial characterization2. Mutagenesis and electrophysiological assessment of conserved and divergent putative mechanosensitive features of OSCA1.2 reveal a selective disruption of the macroscopic currents elicited by poking without considerable effects on stretch-activated currents (SAC). Our results support the involvement of the amphipathic helix and lipid-interacting residues in the membrane fenestration in the response to poking. Our findings position these two structural elements as potential sources of functional diversity within the family.

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Section: Discussionmentioning

confidence: 99%

Structure-guided mutagenesis of OSCAs reveals differential activation to mechanical stimuli

Jojoa-Cruz,

Dubin,

Lee

et al. 2023

Preprint

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“…Structural analyses of OSCAs from Arabidopsis and rice, including AtOSCA1.1, AtOSCA1.2, AtOSCA3.1, and OsOSCA1.2 revealed that OSCA channels in plants form symmetric homodimers with ion permeation within each subunit that are mediated by cytosolic inter-subunit interactions (Jojoa-Cruz et al, 2018;Liu et al, 2018;Zhang et al, 2018b;Maity et al, 2019). In contrast, OSCA homologs in animals, the TMEM63 family of proteins, function as monomeric high-threshold mechanosensitive ion channels with the cytosolic side of the pore plugged by a lipid-like density that needs to be removed to allow ion permeation (Zhang et al, 2023c;Zheng et al, 2023). Generally, OSCA/TMEM63 may respond to the deformation of the local membrane through a lipid-gated mechanism (Zhang et al, 2023c).…”

Section: Sensing Of Membrane Tensionmentioning

confidence: 99%

How plants sense and respond to osmotic stress

Yu,

Chao,

Zhao

2024

JIPB

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Drought is one of the most serious abiotic stresses to land plants. Plants sense and respond to drought stress to survive under water deficiency. Scientists have studied how plants sense drought stress, or osmotic stress caused by drought, ever since Charles Darwin, and gradually obtained clues about osmotic stress sensing and signaling in plants. Osmotic stress is a physical stimulus that triggers many physiological changes at the cellular level, including changes in turgor, cell wall stiffness and integrity, membrane tension, and cell fluid volume, and plants may sense some of these stimuli and trigger downstream responses. In this review, we emphasized water potential and movements in organisms, compared putative signal inputs in cell wall‐containing and cell wall‐free organisms, prospected how plants sense changes in turgor, membrane tension, and cell fluid volume under osmotic stress according to advances in plants, animals, yeasts, and bacteria, summarized multilevel biochemical and physiological signal outputs, such as plasma membrane nanodomain formation, membrane water permeability, root hydrotropism, root halotropism, Casparian strip and suberin lamellae, and finally proposed a hypothesis that osmotic stress responses are likely to be a cocktail of signaling mediated by multiple osmosensors. We also discussed the core scientific questions, provided perspective about the future directions in this field, and highlighted the importance of robust and smart root systems and efficient source‐sink allocations for generating future high‐yield stress‐resistant crops and plants.

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“…Based on the hypothesis that SFO excitatory neurons directly monitor blood osmolality by osmosensitive or mechanosensitive ion channels, we analyzed the expression of the known osmosensitive or mechanosensitive ion channels, including Piezo1/2, TMC1/2 and TMEM63 family channel in these neurons 45,[48][49][50]53,54,[57][58][59][60][61][62][63][64][65][66][67][68] , using published single-cell sequencing data collected from the SFO 17 . We found that TMEM63B mRNA is expressed in SFO excitatory neurons (Figure S2).…”

Section: Sfo Excitatory Neurons Can Be Directly Activated By Osmolari...mentioning

confidence: 99%

“…Our previous study further showed that OSCA family proteins are mechanically activated ion channels 44 , and TMEM63 family proteins, the animal homologs of OSCA, were also shown to be mechano-gated ion channels 45 . The mammalian TMEM63 family has three members, TMEM63A, TMEM63B and TMEM63C, and their osmosensing ability and physiological function in mammals are worthy of studying [45][46][47][48][49][50][51][52][53][54] .…”

Section: Introductionmentioning

confidence: 99%

TMEM63B functions as a mammalian thirst receptor

Zou,

Chen,

Ruan

et al. 2024

Preprint

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Thirst drives animals to reinstate water homeostasis by fluid intake. An increase of blood osmolality is thought to induce thirst by activating a thirst receptor expressed in the subfornical organ (SFO), but the molecular identity of this receptor remains elusive. Here, we provide behavioral and functional evidence to show that TMEM63B functions as a mammalian thirst receptor in the SFO and mediates osmotic and dehydrated thirst. First, we showed that TMEM63B is expressed in SFO excitatory neurons and required for the neuronal responses to hypertonic stimulation. Heterologously expressed TMEM63B is activated by hypertonic stimuli and point mutations can alter the reversal potential of the channel. More importantly, purified TMEM63B in liposomes establishes osmolarity-gated currents. Finally, Tmem63b knockout mice have profound deficits in thirst, and deleting TMEM63B within the SFO neurons recapitulated this phenotype. Taken together, these results provide a molecular basis for thirst and demonstrate TMEM63B is the long-sought mammalian thirst receptor.

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TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels

Cited by 32 publications

References 76 publications

Structure-guided mutagenesis of OSCAs reveals differential activation to mechanical stimuli

Structure-guided mutagenesis of OSCAs reveals differential activation to mechanical stimuli

How plants sense and respond to osmotic stress

TMEM63B functions as a mammalian thirst receptor

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