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

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Abstract

TMEM16F is activated by elevated intracellular Ca²⁺,and functions as a small-conductance ion channel and as a phospholipid scramblase. In contrast to its paralogs, the TMEM16A/B calcium-activated chloride channels, mouse TMEM16F has been reported as a cation-, anion-, or non-selective ion channel, without a definite conclusion. Starting with the Q559K mutant that shows no current rundown and less outward rectification in excised patch, we found that the channel shifted its ion selectivity in response to the change of intracellular Ca²⁺ concentration, with an increased permeability ratio of Cl^- to Na⁺ (P_Cl-/P_Na+) at a higher Ca²⁺ level. The gradual shift of relative ion permeability did not correlate with the channel activation state. Instead, it was indicative of an alteration of electrostatic field in the permeation pathway. The dynamic change of ion selectivity suggests a charge-screening mechanism for TMEM16F ion conduction, and it provides hints to the study of TMEM16F physiological functions.

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All data generated or analysed during this study are included in the manuscript and supporting files

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Wenlei Ye

Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4694-1493
Tina W Han

Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Mu He

Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Yuh Nung Jan

Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1367-6299
Lily Yeh Jan

Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States

For correspondence
Lily.Jan@ucsf.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3938-8498

Funding

National Institute of Neurological Disorders and Stroke (R01NS069229)

Lily Yeh Jan

Jane Coffin Childs Memorial Fund for Medical Research

Tina W Han

Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD089639)

Mu He

Howard Hughes Medical Institute

Yuh Nung Jan
Lily Yeh Jan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.