KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies

Prado, Pablo Ávalos; Häfner, Stephanie; Comoglio, Yannick; Wdziekonski, Brigitte; Duranton, Christophe; Attali, Bernard; Barhanin, Jacques; Sandoz, Guillaume

doi:10.1016/j.cell.2020.11.047

Cited by 21 publications

(11 citation statements)

References 58 publications

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“…Several other possible binding partners of TMEM16 proteins have been reported. Huang et al [58] showed that TMEM16C binds the Na +activated K + channel Slack, increasing the single-channel activity and sodium sensitivity of Slack channels; structural data by Pan et al [59] revealed that TMC1 channels share a common architecture with the TMEM16 channel, raising the possibility that some TMCbinding proteins could also bind TMEM16F; Avalos-Prado et al [60] reported that KCNE1 is an auxiliary subunit of TMEM16A. However, also several other modulators including cholesterol, fatty acids, phosphorylation, have been shown to regulate the activity of some TMEM16 family members [4,61].…”

Section: Ion Selectivitymentioning

confidence: 99%

Anion and Cation Permeability of the Mouse TMEM16F Calcium-Activated Channel

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2021

IJMS

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TMEM16F is involved in several physiological processes, such as blood coagulation, bone development and virus infections. This protein acts both as a Ca2+-dependent phospholipid scramblase and a Ca2+-activated ion channel but several studies have reported conflicting results about the ion selectivity of the TMEM16F-mediated current. Here, we have performed a detailed side-by-side comparison of the ion selectivity of TMEM16F using the whole-cell and inside-out excised patch configurations to directly compare the results. In inside-out configuration, Ca2+-dependent activation was fast and the TMEM16F-mediated current was activated in a few milliseconds, while in whole-cell recordings full activation required several minutes. We determined the relative permeability between Na+ and Cl¯ (PNa/PCl) using the dilution method in both configurations. The TMEM16F-mediated current was highly nonselective, but there were differences depending on the configuration of the recordings. In whole-cell recordings, PNa/PCl was approximately 0.5, indicating a slight preference for Cl¯ permeation. In contrast, in inside-out experiments the TMEM16F channel showed a higher permeability for Na+ with PNa/PCl reaching 3.7. Our results demonstrate that the time dependence of Ca2+ activation and the ion selectivity of TMEM16F depend on the recording configuration.

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Section: Ion Selectivitymentioning

confidence: 99%

Anion and Cation Permeability of the Mouse TMEM16F Calcium-Activated Channel

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2021

IJMS

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“…Association of a ß-subunit such as holoCAM or apoCAM with TMEM16A may not be surprising, given the recent findings of an association of the KCNQ1-K + channel ß-subunit KCNE1 with TMEM16A [48]. Nevertheless, activation of TMEM16A by benzimidazolone compounds and the effects of CAM-regulated CAMKII or calcineurin were very moderate in epithelial cells with endogenous expression of TMEM16A.…”

Section: Discussionmentioning

confidence: 98%

“…Nevertheless, activation of TMEM16A by benzimidazolone compounds and the effects of CAM-regulated CAMKII or calcineurin were very moderate in epithelial cells with endogenous expression of TMEM16A. Taken together, it appears indispensable to examine whether activation by CAM and other accessory proteins/ßsubunits [48], phosphatidylinositols, temperature or small molecule activators, respectively, does exist for endogenous channels expressed in non-cultured cells and tissues under physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

Calmodulin-Dependent Regulation of Overexpressed but Not Endogenous TMEM16A Expressed in Airway Epithelial Cells

et al. 2021

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Regulation of the Ca2+-activated Cl− channel TMEM16A by Ca2+/calmodulin (CAM) is discussed controversially. In the present study, we compared regulation of TMEM16A by Ca2+/calmodulin (holo-CAM), CAM-dependent kinase (CAMKII), and CAM-dependent phosphatase calcineurin in TMEM16A-overexpressing HEK293 cells and TMEM16A expressed endogenously in airway and colonic epithelial cells. The activator of the Ca2+/CAM-regulated K+ channel KCNN4, 1-EBIO, activated TMEM16A in overexpressing cells, but not in cells with endogenous expression of TMEM16A. Evidence is provided that CAM-interaction with TMEM16A modulates the Ca2+ sensitivity of the Cl− channel. Enhanced Ca2+ sensitivity of overexpressed TMEM16A explains its activity at basal (non-elevated) intracellular Ca2+ levels. The present results correspond well to a recent report that demonstrates a Ca2+-unbound form of CAM (apo-CAM) that is pre-associated with TMEM16A and mediates a Ca2+-dependent sensitization of activation (and inactivation). However, when using activators or inhibitors for holo-CAM, CAMKII, or calcineurin, we were unable to detect a significant impact of CAM, and limit evidence for regulation by CAM-dependent regulatory proteins on receptor-mediated activation of endogenous TMEM16A in airway or colonic epithelial cells. We propose that regulatory properties of TMEM16A and and other members of the TMEM16 family as detected in overexpression studies, should be validated for endogenous TMEM16A and physiological stimuli such as activation of phospholipase C (PLC)-coupled receptors.

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“…Recently, Ávalos Padro et al . ( 2021 ) reported that the interaction of TMEM16A with KCNE1 switches the gating mode of TMEM16A from Ca 2+ ‐dependent to voltage‐dependent, showing that TMEM16A could also be activated in the absence of Ca 2+ if it is associated with KCNE1. However, our data show that type II and type III cells lack voltage‐gated Cl – currents also in nominally 0 intracellular Ca 2+ (Fig.…”

Section: Discussionmentioning

confidence: 99%

Functional expression of TMEM16A in taste bud cells

Guarascio

Gonzalez-Velandia

Hernandez-Clavijo

et al. 2021

The Journal of Physiology

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Taste transduction occurs in taste buds in the tongue epithelium -The Ca 2+ -activated Clchannels TMEM16A and TMEM16B play relevant physiological roles in several sensory systems -Here, we report that TMEM16A, but not TMEM16B, is expressed in the apical part of taste buds -Large Ca 2+ -activated Cl − currents blocked by Ani-9, a selective inhibitor of TMEM16A, are measured in type I, but not in type II or III taste cells -ATP indirectly activates Ca 2+ -activated Clcurrents in type I cells through TMEM16A channels -These results indicate that TMEM16A is functional in type I taste cells and contribute to understanding the largely unknown physiological roles of these cells

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KCNE1 is an auxiliary subunit of two distinct ion channel superfamilies

Cited by 21 publications

References 58 publications

Anion and Cation Permeability of the Mouse TMEM16F Calcium-Activated Channel

Anion and Cation Permeability of the Mouse TMEM16F Calcium-Activated Channel

Calmodulin-Dependent Regulation of Overexpressed but Not Endogenous TMEM16A Expressed in Airway Epithelial Cells

Functional expression of TMEM16A in taste bud cells

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