Dynamic change of electrostatic field in TMEM16F permeation pathway shifts its ion selectivity

Ye, Wenlei; Han, Tina W.; He, Mu; Jan, Yuh Nung

doi:10.7554/elife.45187

Cited by 26 publications

(37 citation statements)

References 55 publications

(142 reference statements)

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“…As a control, we examined the pH i sensitivity of Q559K, a mutation of the pore lining residue Q559 that affects TMEM16F ion selectivity without obvious effect on Ca 2+ binding (Fig. 7A) (Yang et al ., 2012; Ye et al ., 2019). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Molecular underpinning of intracellular pH regulation on TMEM16F

Liang¹,

Yang

2020

Preprint

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39TMEM16F, a dual functional phospholipid scramblase and ion channel, is important in blood 40 coagulation, skeleton development, HIV infection and cell fusion. Despite the advances in 41 understanding its structure and activation mechanism, how TMEM16F is regulated by intracellular 42 factors remains largely elusive. Here we report that TMEM16F lipid scrambling and ion channel 43 activities are strongly influenced by intracellular pH (pHi). We find that low pHi attenuates 44 whereas high pHi potentiates TMEM16F activation. Our biophysical characterizations pinpoint 45 that the pHi regulatory effects on TMEM16F stem from protonation and deprotonation of the Ca 2+ 46 binding sites, which in turn reduces and enhances Ca 2+ binding affinity, respectively. We further 47 demonstrate that intracellular alkalization of 0.5 pHi can significantly promote TMEM16F 48 activities in a choriocarcinoma cell line. Our findings thus uncover a regulatory mechanism of 49 TMEM16F by pHi and shine light on understanding the pathophysiological roles of TMEM16F in 50 diseases with dysregulated pHi including cancer. 51 52

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Section: Resultsmentioning

confidence: 99%

Molecular underpinning of intracellular pH regulation on TMEM16F

Liang¹,

Yang

2020

Preprint

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“…Alternative splicing further increases the number of isoforms with different biophysical properties and expression (Ferrera et al, 2009;Mazzone et al, 2011;Ertongur-Fauth et al, 2014). Ano1, 2, and 6 have been shown to convey Ca 2+ -activated Cl − conductances, although Ano6 can conduct both anions and cations depending on intracellular Ca 2+ concentration and membrane potential (Caputo et al, 2008;Schroeder et al, 2008;Yang et al, 2008;Pifferi et al, 2009;Ye et al, 2019). Ano conductances are synergistically regulated by intracellular Ca 2+ , membrane depolarization, membrane lipids and heat (Cho et al, 2012;Schreiber et al, 2018;Le et al, 2019;Lin et al, 2019).…”

Section: Calcium-activated Chloride Channelsmentioning

confidence: 99%

Chloride – The Underrated Ion in Nociceptors

et al. 2020

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In contrast to pain processing neurons in the spinal cord, where the importance of chloride conductances is already well established, chloride homeostasis in primary afferent neurons has received less attention. Sensory neurons maintain high intracellular chloride concentrations through balanced activity of Na +-K +-2Cl − cotransporter 1 (NKCC1) and K +-Cl − cotransporter 2 (KCC2). Whereas in other cell types activation of chloride conductances causes hyperpolarization, activation of the same conductances in primary afferent neurons may lead to inhibitory or excitatory depolarization depending on the actual chloride reversal potential and the total amount of chloride efflux during channel or transporter activation. Dorsal root ganglion (DRG) neurons express a multitude of chloride channel types belonging to different channel families, such as ligand-gated, ionotropic γ-aminobutyric acid (GABA) or glycine receptors, Ca 2+-activated chloride channels of the anoctamin/TMEM16, bestrophin or tweetyhomolog family, CLC chloride channels and transporters, cystic fibrosis transmembrane conductance regulator (CFTR) as well as volume-regulated anion channels (VRACs). Specific chloride conductances are involved in signal transduction and amplification at the peripheral nerve terminal, contribute to excitability and action potential generation of sensory neurons, or crucially shape synaptic transmission in the spinal dorsal horn. In addition, chloride channels can be modified by a plethora of inflammatory mediators affecting them directly, via protein-protein interaction, or through signaling cascades. Since chloride channels as well as mediators that modulate chloride fluxes are regulated in pain disorders and contribute to nociceptor excitation and sensitization it is timely and important to emphasize their critical role in nociceptive primary afferents in this review.

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“…The precise permeation pathway underlying large molecule permeation of component 2 is currently unknown, but may involve the TMEM16F pore as it functions as a poorly selective ion channel 40,44 , enabling the passage of small organic cations, such as NMDG + (ref. 40 ).…”

Section: Discussionmentioning

confidence: 99%

P2X7 Receptors and TMEM16 Channels Form a Hub with Implications for Macropore Formation and Current Facilitation

Dunning

Martz

Peralta

et al. 2021

Preprint

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P2X7 receptors (P2X7) are cationic channels involved in many diseases. They exhibit unique behaviors, such as “macropore” formation, which corresponds to enhanced large molecule cell membrane permeability, and current facilitation, which is caused by prolonged activation. These two phenomena have often been confounded, but thus far no clear mechanisms have been resolved. Here we provide evidence that current facilitation and macropore formation involve functional complexes comprised of P2X7 and TMEM16, a family of Ca2+-activated ion channel/scramblases. We found that current facilitation results in an increase of complex-embedded P2X7 open channel probability, a result mimicked by plasma membrane cholesterol depletion. We further show that macropore formation entails two distinct large molecule permeation components, one of which requires protein complexes featuring TMEM16F subtype, the other likely being direct permeation through the P2X7 pore itself. Such protein complexes can be considered to represent a regulatory hub intimately involved in distinct P2X7 functionalities.

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Dynamic change of electrostatic field in TMEM16F permeation pathway shifts its ion selectivity

Cited by 26 publications

References 55 publications

Molecular underpinning of intracellular pH regulation on TMEM16F

Molecular underpinning of intracellular pH regulation on TMEM16F

Chloride – The Underrated Ion in Nociceptors

P2X7 Receptors and TMEM16 Channels Form a Hub with Implications for Macropore Formation and Current Facilitation

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