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Functional roles of glutamic acid E143 and E705 residues in the N-terminus and transmembrane domain 7 of Anoctamin 1 in calcium and noxious heat sensing.
Jonghyun Choi1,#, Yongwoo Jang2,#, Haedong Kim1, Jungwon Wee2, Sinyoung Cho1, Woo Sung Son1, Sung Min Kim4,5,*, Young Duk Yang1,*
1College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Sungnam, Gyunggi, 463-840, Korea,
2Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA.,
3Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea,
4Department of Physical Education, College of Performing Arts and Sport and 5Department of Active Aging Industry, Graduate School, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 133-791, South Korea
Abstract
Anoctamin 1 is an anion channel that is activated by changes in cytosolic Ca2+ concentration and noxious heat. Although the critical roles of ANO1 have been elucidated in various cell types, the control of its gating mechanisms by Ca2+ and heat remain more elusive. To investigate critical amino acid residues for modulation of Ca2+ and heat sensing, we constructed a randomized mutant library for ANO1. Among 695 random mutants, reduced Ca2+ sensitivity was observed in two mutants (mutant 84 and 87). Consequently, the E143A mutant showed reduced sensitivity to Ca2+ but not to high temperatures, whereas the E705V mutant exhibited reduced sensitivity to both Ca2+ and noxious heat. These results suggest that the glutamic acids (E) at 143 and 705 residues in ANO1 are critical for modulation of Ca2+ and/or heat responses. Furthermore, these findings help to provide a better understanding of the Ca2+-mediated activation and heat-sensing mechanism of ANO1.
Abstract, Accepted Manuscript(in press) [Submitted on October 20, 2017, Accepted on January 5, 2018]
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