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Updated: Sep 5, 2025

A Proteoliposome-Based Efflux Assay to Determine Single-molecule Properties of Cl- Channels and Transporters
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A Proteoliposome-Based Efflux Assay to Determine Single-molecule Properties of Cl- Channels and Transporters

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Structure and Function of Calcium-Activated Chloride Channels and Phospholipid Scramblases in the TMEM16 Family

Dung Manh Nguyen1,2, Tsung-Yu Chen3

  • 1Center for Neuroscience, University of California, Davis, CA, USA. dunguyen@som.umaryland.edu.

Handbook of Experimental Pharmacology
|July 6, 2022
PubMed

Insights

The transmembrane protein 16 (TMEM16) family includes calcium-activated chloride channels and phospholipid scramblases. Their structure features a unique transport pathway potentially lined by phospholipids, influencing function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • The transmembrane protein 16 (TMEM16) family comprises proteins with diverse functions, including calcium-activated chloride channel activity and phospholipid scrambling.
  • Ten mammalian TMEM16 proteins (TMEM16A-K, excluding TMEM16I) and non-mammalian homologs (e.g., afTMEM16, nhTMEM16) have been identified.

Approach:

  • This review synthesizes current knowledge on the structure and function of TMEM16 proteins.
  • Analysis of the conserved structural features, including transmembrane helices, calcium-binding sites, and transport pathways.

Key Points:

  • TMEM16 proteins are homodimers, with each subunit possessing ten transmembrane helices.
  • A single ion-permeation/phospholipid transport pathway exists per subunit, characterized by distinct vestibules and a narrow neck.
  • The transport pathway lining may involve membrane phospholipids, suggesting variable biophysical properties and activation mechanisms across the TMEM16 family.

Conclusions:

  • Understanding the structural basis of TMEM16 function is crucial for elucidating their roles in cellular processes.
  • Variations in pathway composition and structure likely contribute to the functional diversity observed within the TMEM16 family.
Keywords:
Calcium-activated chloride channelsGatingPermeationPhospholipid scramblasesTMEM16

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