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Calmodulin-dependent activation of the epithelial calcium-dependent chloride channel TMEM16A

Yuemin Tian1, Patthara Kongsuphol, Martin Hug

  • 1Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|December 1, 2010
PubMed

Insights

The transmembrane protein TMEM16A, crucial for calcium-activated chloride channels, requires cytoskeletal interaction and calmodulin for full activation. This finding offers new therapeutic strategies for diseases like cystic fibrosis.

Area of Science:

  • Physiology
  • Molecular Biology
  • Cell Biology

Background:

  • Transmembrane protein 16A (TMEM16A), also known as anoctamin 1 (Ano1), is a key component of calcium-activated chloride channels.
  • TMEM16A dysfunction leads to severe physiological defects, including impaired epithelial transport and early mortality in mice.

Purpose of the Study:

  • To elucidate the activation mechanisms of TMEM16A, particularly the role of calcium and associated proteins.
  • To investigate the necessity of direct calcium binding versus intermediary factors for TMEM16A channel function.

Main Methods:

  • Cellular localization studies of TMEM16A.
  • Investigation of TMEM16A activation requirements, including cytosolic ATP, phosphorylation, and calmodulin interaction.
  • Functional assays using TMEM16A activators like 1-EBIO, DCEBIO, and riluzole.

Main Results:

  • TMEM16A is localized to the cell membrane and requires cytoskeletal interactions for full activation.
  • Cytosolic ATP is necessary, but protein kinase phosphorylation is not required for TMEM16A activation.
  • Calmodulin, a calcium-binding protein, physically interacts with TMEM16A and is indispensable for its function.
  • Compounds known to activate calmodulin-interacting potassium channels also activate TMEM16A.

Conclusions:

  • TMEM16A activation is a complex process involving membrane localization, cytoskeletal association, and calmodulin binding.
  • These findings highlight calmodulin as a critical mediator in TMEM16A channel function.
  • The identified activators offer potential therapeutic agents for conditions involving defective electrolyte secretion, such as cystic fibrosis.

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