Christian J Peters1, John M Gilchrist2, Jason Tien2, Neville P Bethel3, Lijun Qi2, Tingxu Chen2, Lynn Wang2, Yuh Nung Jan4, Michael Grabe3, Lily Y Jan5. 1. Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: christian.peters@ucsf.edu. 2. Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA. 3. Department of Pharmaceutical Chemistry and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA. 4. Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA. 5. Departments of Physiology, Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: lily.jan@ucsf.edu.
Abstract
Calcium-activated chloride channels (CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating. Here, we report that voltage modulation of TMEM16A-CaCC involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment.
Calcium-activated chloride channels (pan class="Gene">CaCCs) formed by TMEM16A or TMEM16B are broadly expressed in the nervous system, smooth muscles, exocrine glands, and other tissues. With two calcium-binding sites and a pore within each monomer, the dimeric CaCC exhibits voltage-dependent calcium sensitivity. Channel activity also depends on the identity of permeant anions. To understand how CaCC regulates neuronal signaling and how CaCC is, in turn, modulated by neuronal activity, we examined the molecular basis of CaCC gating. Here, we report that voltage modulation of TMEM16A-CaCC involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment.
Authors: Jeffery B Klauda; Richard M Venable; J Alfredo Freites; Joseph W O'Connor; Douglas J Tobias; Carlos Mondragon-Ramirez; Igor Vorobyov; Alexander D MacKerell; Richard W Pastor Journal: J Phys Chem B Date: 2010-06-17 Impact factor: 2.991
Authors: Jason Tien; Hye Young Lee; Daniel L Minor; Yuh Nung Jan; Lily Yeh Jan Journal: Proc Natl Acad Sci U S A Date: 2013-04-01 Impact factor: 11.205
Authors: Tina W Han; Wenlei Ye; Neville P Bethel; Mario Zubia; Andrew Kim; Kathy H Li; Alma L Burlingame; Michael Grabe; Yuh Nung Jan; Lily Y Jan Journal: Proc Natl Acad Sci U S A Date: 2019-01-08 Impact factor: 11.205