TMEM150C/Tentonin3 Is a Regulator of Mechano-gated Ion Channels

Abstract

SUMMARY Neuronal mechano-sensitivity relies on mechanogated ion channels, but pathways regulating their activity remain poorly understood. TMEM150C was proposed to mediate mechano-activated current in proprioceptive neurons. Here, we studied functional interaction of TMEM150C with mechano-gated ion channels from different classes (Piezo2, Piezo1, and the potassium channel TREK-1) using two independent methods of mechanical stimulation. We found that TMEM150C significantly prolongs the duration of the mechano-current produced by all three channels, decreases apparent activation threshold in Piezo2, and induces persistent current in Piezo1. We also show that TMEM150C is co-expressed with Piezo2 in trigeminal neurons, expanding its role beyond proprioceptors. Finally, we cloned TMEM150C from the trigeminal neurons of the tactile-foraging domestic duck and showed that it functions similarly to the mouse ortholog, demonstrating evolutionary conservation among vertebrates. Our studies reveal TMEM150C as a general regulator of mechano-gated ion channels from different classes.

Piezo2 integrates mechanical and thermal cues in vertebrate mechanoreceptors

“…Mutations that affect inactivation in either channel are linked to disease, and thus the timing of this process has physiological importance (9,(62)(63)(64). Inactivation is influenced by cellular factors and is thought to involve a hydrophobic gate formed primarily by the inner helices plus other regions including the extracellular cap (23,61,(65)(66)(67)(68). Whether inactivation is governed by changes in plasma membrane properties is unclear.…”

“…HEK293T ΔP1 , N2A ΔP1 (27,38) and ND7/23 cells were cultured using standard procedures. Duck-Piezo2-pMO and Mouse-Piezo1-pMO were described previously (67). Squirrel Piezo2 was amplified from squirrel DRG cDNA and deposited into the GenBank database (accession no.…”

TACAN is an essential component of the mechanosensitive ion channel responsible for pain sensing

“…To determine if this increase in cell mechanosensitivity occurs in other cell types, we examined the effect of TACAN expression on mechanically-evoked currents in COS-7 and HEK293 cells (HEK293/17) ( Figures S3A-S3D), which are commonly used to study MSCs (Anderson et al, 2018;Coste et al, 2010;Li Fraine et al, 2017). In MOCK-transfected COS7 cells, we observed the presence of endogenous MSCs ( Figure S3A, left panel) with a low activation threshold, often as low as -5 mm Hg (mean activation threshold: -21.3 ± 1.6 mm Hg, n=97), consistent with previous reports (Sharif-Naeini et al, 2009).…”

“…It was recently suggested that some candidate MSCs may act as permissive factors that promote the expression or membrane targeting of the endogenous channel (Anderson et al, 2018;Dubin et al, 2017). Alternatively, they may need additional subunits to form a functional ion channel.…”

Inactivation Kinetics and Mechanical Gating of Piezo1 Ion Channels Depend on Subdomains within the Cap

“…Inactivation modulates mechanical sensitivity and endows Piezos with the ability to function as frequency filters of repetitive stimuli, though the physiological implications of these findings have yet to be explored (Lewis et al, 2017;Lewis and Grandl, 2015). Regulation of inactivation occurs through many mechanisms, including alternative splicing, pH, temperature, divalent ions, osmotic swelling, co-expression of other membrane proteins, membrane lipid composition, and G-protein-coupled pathways (Anderson et al, 2018;Bae et al, 2015;Dubin et al, 2012;Eijkelkamp et al, 2013;Gottlieb and Sachs, 2012;Jia et al, 2013;Romero et al, 2019;Szczot et al, 2017;Zheng et al, 2019b). Moreover, mutations in both Piezo1 and Piezo2 have been identified in human patients diagnosed with xerocytosis and distal arthrogryposis that cause a gain-of-function phenotype by slowing inactivation, indicating that normal physiology requires inactivation to be intact (Albuisson et al, 2013;Bae et al, 2013;Coste et al, 2013;Zarychanski et al, 2012).…”