8.A.113. The Tentonin or TMEM150 (TMEM150) Family
Touch sensation or proprioception requires the transduction of mechanical stimuli into electrical signals by mechanoreceptors. These mechanoreceptors involve transducer channels. Although Piezo1 and 2 are mechanically activated (MA) channels with rapid inactivation, MA molecules with slow inactivation kinetics exist. TMEM150c has been reported to either be a channel protein or a Piezo channel protein modifiier. Hong et al. 2016 reported that heterologously expressed Tentonin3 (TTN3)/TMEM150C is activated by mechanical stimuli with slow inactivation kinetics. Genetic ablation of Ttn3/Tmem150c markedly reduced slowly adapting neurons in dorsal-root ganglion neurons. The MA TTN3 currents were inhibited by known blockers of mechanosensitive ion channels, and TTN3 was localized in muscle spindle afferents. Ttn3-deficient mice exhibited the loss of coordinated movements and abnormal gait. Thus, TTN3 appears to be a component of a mechanosensitive channel with a slow inactivation rate and contributes to motor coordination (Hong et al. 2016). Dubin et al. 2017 showed that if Piezo1 was deleted in mice, no such current was observed. However, Hong et al. 2017 concluded that TTN3 is a channel protein, but Anderson et al. 2018 reported functional interaction of TMEM150C with mechano-gated ion channels from different classes (Piezo2, Piezo1, and the potassium channel TREK-1). TMEM150C significantly prolongs the duration of the mechano-current produced by all three channels, decreases the apparent activation threshold in Piezo2, and induces persistent current in Piezo1. They also showed that TMEM150C is co-expressed with Piezo2 in trigeminal neurons, expanding its role beyond proprioceptors (Anderson et al. 2018). It should be noted that this controversy in not yet resolved. For example, Ojeda-Alonso et al. 2022 could not demonstrate channel activity for TMEM150, but Kang and Lee 2024 confirmed its channel activity and examined its structure. Purified TTN3 proteins incorporated into the lipid bilayer displayed spontaneous and pressure-sensitive channel currents. These MA currents were conserved across vertebrates and differ from Piezo1 in activation threshold and pharmacological responses. Deep neural network structure prediction programs coupled with mutagenetic analysis predicted a rectangular-shaped, tetrameric structure with six transmembrane helices and a pore at the inter-subunit center. The putative pore aligned with two helices of each subunit and had constriction sites whose mutations changed the MA currents (Pak et al. 2024).
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TMEM150c/Tentonin 3 of 249 aas and 6 TMSs. According to Anderson et al. 2018, it reglulates channels such as Piezo 1 and Piezo 2. According to Hong et al. 2017, it has inherent channel activity, but Ojeda-Alonso et al. 2022 could not demonstrate this, Nevertheless, Pak et al. 2024 showed that tentonin 3 is a pore-forming subunit of a slow inactivation mechanosensitive channel. They reported that tentonin 3/TMEM150C (TTN3) confers mechanically activating (MA) currents with slow inactivation kinetics in somato- and barosensory neurons. Thus, purified TTN3 proteins incorporated into the lipid bilayer displayed spontaneous and pressure-sensitive channel currents. These MA currents were conserved across vertebrates and differ from Piezo1 in activation threshold and pharmacological response. Deep neural network structure prediction programs coupled with mutagenetic analysis predicted a rectangular-shaped, tetrameric structure with six transmembrane helices and a pore at the inter-subunit center. The putative pore aligned with two helices of each subunit and had constriction sites whose mutations changed the MA currents. These findings suggest that TTN3 is a pore-forming subunit of a distinct slow inactivation MA channel, potentially possessing a tetrameric structure (Pak et al. 2024). It appears that Tentonin 3 may both modify some channels and be one as well. Kang and Lee 2024 have confirmed the ion channel activity of tentonin and examined its structure.
TMEM150c of Homo sapiens
TMEM150a of 271 aas and 6 TMSs. Regulates localization of phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (Chung et al. 2015). Acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns4P) synthesis (Chung et al. 2015). May also play a role in fasting-induced catabolism.
TMEM150a of Homo sapiens
TMEM150b of 233 aas and 6 TMSs. Modulator of macroautophagy that causes accumulation of autophagosomes under basal conditions and enhances autophagic flux. Represses cell death and promotes long-term clonogenic survival of cells grown in the absence of glucose in a macroautophagy-independent manner (Mrschtik et al. 2015). May have some role in extracellular matrix engulfment or growth factor receptor recycling, both of which can modulate cell survival.
TMEM150b of Homo sapiens
Uncharacterized TMEM150 homologue of 252 aas and 6 TMSs.
UP of Schistosoma japonicum (Blood fluke)
Uncharacterized DNA damage-regulated autophagy modulator protein 2 of 243 aas and 6 TMSs.
UP of Anoplophora glabripennis (Asian longhorned beetle)
Uncharacterized TMEM150b-like protein of 251 aas and 6 TMSs.
UP of Branchiostoma belcheri (Belcher's lancelet) Isolated from sea water.
Uncharacterized protein of 268 aas and 6 TMSs.
UP of Pristionchus pacificus (Parasitic nematode)
DNA damage-regulated autophagy modulator protein 1, DRAM1, of 238 aas and 6 TMSs. It is found in the membranes of intracellular organelles including lysosomes, the ER and the golgi apparatus. Loss results in golgi fragmentation (Wei et al. 2019).
DRAM1 of Homo sapiens
DRAM2 or TMEM77 of 266 aas and 6 TMSs. In the retina, might be involved in the process of photoreceptor cells renewal and recycling to preserve visual function (El-Asrag et al. 2015). Induces apoptotic cell death when coexpressed with DRAM1 (TC# 8/A/113/1/8) (Park et al. 2009).
DRAM2 of Homo sapiens