TMEM120A/TACAN inhibits mechanically activated Piezo2 channels

Abstract

Mechanically activated Piezo2 channels are key mediators of light touch and proprioception in mice and humans. Relatively little is known about what other proteins regulate Piezo2 activity in a cellular context. TACAN (TMEM120A) was proposed to act as a high threshold mechanically activated ion channel in nociceptive dorsal root ganglion (DRG) neurons. Here we find that TACAN co-expression robustly reduced mechanically activated Piezo2 currents, but did not inhibit mechanically activated Piezo1 and TREK1 currents. TACAN co-expression did not affect cell surface expression of either Piezo1 or Piezo2 and did not have major effects on the cortical actin or tubulin cytoskeleton. TACAN expression alone did not result in the appearance of mechanically activated currents above background. In addition, TACAN and Piezo2 expression in DRG neurons overlapped, and siRNA mediated knockdown of TACAN did not decrease the proportion of slowly adapting mechanically activated currents, but resulted in an increased proportion of rapidly adapting currents. Our data do not support TACAN being a mechanically activated ion channel, and identify it as a negative modulator of Piezo2 channel activity.

Regulation of the PKD2 Channel Function by TACAN

“…Structural studies found that TACAN structure resembles that of the long-chain fatty acid elongase 7 (Ke et al, 2021; Niu et al, 2021; Rong et al, 2021; Xue et al, 2021), suggesting the possibility that TACAN may act as an enzyme. In addition to our current finding, TACAN was previously reported to be an inhibitor of Piezo2, but not Piezo1 or TREK-1, but with an unclear mechanism of inhibition (Del Rosario et al, 2021).…”

“…However, when they were expressed in CHO cells, only TACAN induced mechano-sensitive currents (Beaulieu-Laroche et al, 2020). TACAN, but not TMEM120B, was reported to inhibit the Piezo2 channel function (Del Rosario et al, 2021). It will be of interest to determine whether TMEM120B regulates the PKD2 function in future studies.…”

“…The report that TACAN acts as an ion channel has been challenged by recent structural and functional studies (Beaulieu-Laroche et al, 2020; Del Rosario et al, 2021; Ke et al, 2021; Niu et al, 2021; Parpaite et al, 2021; Rong et al, 2021; Xue et al, 2021). However, the concept that TACAN is an ion channel is supported by a recent report showing that a point mutation at a candidate pore gate residue significantly increases the channel activity (Chen et al, 2021) and that, by molecular dynamic simulations, each TACAN monomer contains an ion conducting pathway but multiple subunits might be required for TACAN to form a functional ion channel.…”

“…TMEM120A (transmembrane protein 120A, also called TACAN) was initially reported as a nuclear envelope transmembrane protein critical for adipocyte differentiation (Batrakou et al, 2015). It was recently shown to form a mechano-sensitive ion channel sensing the pain (Beaulieu-Laroche et al, 2020), but this was challenged by subsequent structural and functional studies (Del Rosario et al, 2021; Ke et al, 2021; Niu et al, 2021; Parpaite et al, 2021; Rong et al, 2021; Xue et al, 2021). Global knockout of TACAN led to embryo death indicating its importance for embryonic development (Beaulieu-Laroche et al, 2020).…”

The curious case of TMEM120A: Mechanosensor, fat regulator, or antiviral defender?

“…There is also new evidence supporting the mechanosesning function of TMEM120A, such as that TMEM120A negatively regulates the channel activity of Piezo2 in mouse to mediate its mechanosensitivity. [ 28 ] It follows that a comprehensive study on molecules interacting with TMEM120A is important to uncover its cellular functions.…”