BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Cytosolic domain regulates the calcium sensitivity and surface expression of BEST1 channels in the HEK293 cells

  • Kwon Woo Kim (Neurovascular Research Group, Korea Brain Research Institute (KBRI)) ;
  • Junmo Hwang (Neurovascular Research Group, Korea Brain Research Institute (KBRI)) ;
  • Dong-Hyun Kim (Neurovascular Research Group, Korea Brain Research Institute (KBRI)) ;
  • Hyungju Park (Neurovascular Research Group, Korea Brain Research Institute (KBRI)) ;
  • Hyun-Ho Lim (Neurovascular Research Group, Korea Brain Research Institute (KBRI))
  • Received : 2022.10.24
  • Accepted : 2023.01.02
  • Published : 2023.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

BEST family is a class of Ca2+-activated Cl- channels evolutionary well conserved from bacteria to human. The human BEST paralogs (BEST1-BEST4) share significant amino acid sequence homology in the N-terminal region, which forms the transmembrane helicases and contains the direct calcium-binding site, Ca2+-clasp. But the cytosolic C-terminal region is less conserved in the paralogs. Interestingly, this domain-specific sequence conservation is also found in the BEST1 orthologs. However, the functional role of the C-terminal region in the BEST channels is still poorly understood. Thus, we aimed to understand the functional role of the C-terminal region in the human and mouse BEST1 channels by using electrophysiological recordings. We found that the calcium-dependent activation of BEST1 channels can be modulated by the C-terminal region. The C-terminal deletion hBEST1 reduced the Ca2+-dependent current activation and the hBEST1-mBEST1 chimera showed a significantly reduced calcium sensitivity to hBEST1 in the HEK293 cells. And the C-terminal domain could regulate cellular expression and plasma membrane targeting of BEST1 channels. Our results can provide a basis for understanding the C-terminal roles in the structure-function of BEST family proteins.

Keywords

Acknowledgement

We thank the members of the Lim laboratory for their timely help throughout the study. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) grants (2021R1A2C1004884 to H.-H.L.) and the Brain Research Program of the NRF (2020 M3E5D9079 to H.-H.L.) funded by the Ministry of Science and ICT, Republic of Korea, and the KBRI basic research program through Korea Brain Research Institute funded by the Ministry of Science and ICT (22-BR-01-02 to H.-H.L.).

References

  1. Hartzell HC, Qu Z, Yu K, Xiao Q and Chien LT (2008) Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol Rev 88, 639-672  https://doi.org/10.1152/physrev.00022.2007
  2. Hagen AR, Barabote RD and Saier MH (2005) The bestrophin family of anion channels: identification of prokaryotic homologues. Mol Membr Biol 22, 291-302  https://doi.org/10.1080/09687860500129711
  3. Owji AP, Kittredge A, Zhang Y and Yang T (2021) Structure and function of the bestrophin family of calciumactivated chloride channels. Channels (Austin) 15, 604-623  https://doi.org/10.1080/19336950.2021.1981625
  4. Woo DH, Han KS, Shim JW et al (2012) TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell 151, 25-40  https://doi.org/10.1016/j.cell.2012.09.005
  5. Jo S, Yarishkin O, Hwang YJ et al (2014) GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. Nat Med 20, 886-896  https://doi.org/10.1038/nm.3639
  6. Koh W, Park M, Chun YE et al (2022) Astrocytes render memory flexible by releasing D-serine and regulating NMDA receptor tone in the hippocampus. Biol Psychiatry 91, 740-752  https://doi.org/10.1016/j.biopsych.2021.10.012
  7. Tsunenari T, Sun H, Williams J et al (2003) Structure-function analysis of the bestrophin family of anion channels. J Biol Chem 278, 41114-41125  https://doi.org/10.1074/jbc.M306150200
  8. Sun H, Tsunenari T, Yau KW and Nathans J (2002) The vitelliform macular dystrophy protein defines a new family of chloride channels. Proc Natl Acad Sci U S A 99, 4008-4013  https://doi.org/10.1073/pnas.052692999
  9. Qu Z, Cui Y and Hartzell C (2006) A short motif in the C-terminus of mouse bestrophin 3 [corrected] inhibits its activation as a Cl channel. FEBS Lett 580, 2141-2146  https://doi.org/10.1016/j.febslet.2006.03.025
  10. Qu ZQ, Yu K, Cui YY, Ying C and Hartzell C (2007) Activation of bestrophin Cl- channels is regulated by C-terminal domains. J Biol Chem 282, 17460-17467  https://doi.org/10.1074/jbc.M701043200
  11. Kane Dickson V, Pedi L and Long SB (2014) Structure and insights into the function of a Ca2+-activated Cl- channel. Nature 516, 213-218  https://doi.org/10.1038/nature13913
  12. Miller AN, Vaisey G and Long SB (2019) Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin. Elife 8, e43231 
  13. Owji AP, Zhao Q, Ji C et al (2020) Structural and functional characterization of the bestrophin-2 anion channel. Nat Struct Mol Biol 27, 382-391  https://doi.org/10.1038/s41594-020-0402-z
  14. Owji AP, Wang J, Kittredge A et al (2022) Structures and gating mechanisms of human bestrophin anion channels. Nat Commun 13, 3836 
  15. Simonyan V, Chumakov K, Dingerdissen H et al (2016) High-performance integrated virtual environment (HIVE): a robust infrastructure for next-generation sequence data analysis. Database (Oxford) 2016, baw022  https://doi.org/10.1093/database/baw022
  16. Hwang J, Park K, Lee GY et al (2021) Transmembrane topology and oligomeric nature of an astrocytic membrane protein, MLC1. Open Biol 11, 210103 
  17. Chun E, Thompson AA, Liu W et al (2012) Fusion partner toolchest for the stabilization and crystallization of G protein-coupled receptors. Structure 20, 967-976  https://doi.org/10.1016/j.str.2012.04.010
  18. Xiao Q, Prussia A, Yu K, Cui YY and Hartzell HC (2008) Regulation of bestrophin Cl channels by calcium: role of the C terminus. J Gen Physiol 132, 681-692  https://doi.org/10.1085/jgp.200810056
  19. Zhang Y, Kittredge A, Ward N, Ji C, Chen S and Yang T (2018) ATP activates bestrophin ion channels through direct interaction. Nat Commun 9, 3126 
  20. O'Driscoll KE, Leblanc N, Hatton WJ and Britton FC (2009) Functional properties of murine bestrophin 1 channel. Biochem Biophys Res Commun 384, 476-481 https://doi.org/10.1016/j.bbrc.2009.05.008