Expression cloning of TMEM16A as a calcium-activated chloride channel subunit
Björn Christian Schroeder1, Tong Cheng, Yuh Nung Jan
1Department of Physiology, Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA 94143, USA.
Abstract:
Calcium-activated chloride channels (CaCCs) are major regulators of sensory transduction, epithelial secretion, and smooth muscle contraction. Other crucial roles of CaCCs include action potential generation in Characean algae and prevention of polyspermia in frog egg membrane. None of the known molecular candidates share properties characteristic of most CaCCs in native cells. Using Axolotl oocytes as an expression system, we have identified TMEM16A as the Xenopus oocyte CaCC. The TMEM16 family of "transmembrane proteins with unknown function" is conserved among eukaryotes, with family members linked to tracheomalacia (mouse TMEM16A), gnathodiaphyseal dysplasia (human TMEM16E), aberrant X segregation (a Drosophila TMEM16 family member), and increased sodium tolerance (yeast TMEM16). Moreover, mouse TMEM16A and TMEM16B yield CaCCs in Axolotl oocytes and mammalian HEK293 cells and recapitulate the broad CaCC expression. The identification of this new family of ion channels may help the development of CaCC modulators for treating diseases including hypertension and cystic fibrosis.
Insights
Researchers identified TMEM16A as a calcium-activated chloride channel (CaCC) in Xenopus oocytes. This discovery advances understanding of ion channel function and potential treatments for diseases like cystic fibrosis.
Area of Science:
- Molecular Biology
- Ion Channel Physiology
Background:
- Calcium-activated chloride channels (CaCCs) are vital for cellular processes like sensory transduction and secretion.
- Existing molecular candidates do not fully explain native CaCC properties.
Purpose of the Study:
- To identify the molecular identity of CaCCs in Xenopus oocytes.
- To characterize the TMEM16 family as a novel class of CaCCs.
Main Methods:
- Heterologous expression of TMEM16A in Axolotl oocytes.
- Functional characterization of TMEM16A and TMEM16B in oocytes and HEK293 cells.
Main Results:
- TMEM16A was identified as the Xenopus oocyte CaCC.
- TMEM16A and TMEM16B successfully expressed functional CaCCs in multiple cell types.
- The TMEM16 family is conserved and linked to various biological functions and diseases.
Conclusions:
- The TMEM16 family represents a novel class of CaCCs.
- This finding opens avenues for developing CaCC modulators for diseases such as hypertension and cystic fibrosis.
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