Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function

The Journal of General Physiology
Toshiki Yamada, Kevin Strange

Abstract

The volume-regulated anion channel (VRAC) is expressed ubiquitously in vertebrate cells and mediates swelling-induced release of Cl- and organic solutes. Recent studies by several laboratories have demonstrated conclusively that VRAC is encoded by members of the leucine-rich repeat containing 8 (Lrrc8) gene family, which comprises five members, termed Lrrc8a-e. Numerous observations indicate that VRAC is a heteromeric channel comprising the essential subunit LRRC8A and one or more of the other LRRC8 paralogs. Here we demonstrate that the intracellular loop (IL) connecting transmembrane domains 2 and 3 of LRRC8A and the first extracellular loop (EL1) connecting transmembrane domains 1 and 2 of LRRC8C, LRRC8D, or LRRC8E are both essential for VRAC activity. We generate homomeric VRACs by replacing EL1 of LRRC8A with that of LRRC8C and demonstrate normal regulation by cell swelling and shrinkage. We also observe normal volume-dependent regulation in VRAC homomers in which the IL of LRRC8C, LRRC8D, or LRRC8E is replaced with the LRRC8A IL. A 25-amino acid sequence unique to the LRRC8A IL is sufficient to generate homomeric VRAC activity when inserted into the corresponding region of LRRC8C and LRRC8E. LRRC8 chimeras containing thes...Continue Reading

References

Nov 1, 1996·Current Biology : CB·J J Wine, D B Luckie
Feb 1, 2003·Acta Physiologica Scandinavica·B Nilius, G Droogmans
Jun 1, 2005·Biochimica Et Biophysica Acta·Pauline Phelan
Sep 15, 2005·Biochemistry·Christopher J OldfieldA Keith Dunker
Aug 29, 2006·Journal of Molecular Biology·Amrita MohanVladimir N Uversky
Jan 8, 2009·Physiological Reviews·Else K HoffmannStine F Pedersen
Apr 3, 2009·Nature·Shoji MaedaTomitake Tsukihara
Oct 13, 2010·The Journal of General Physiology·Junjie Wang, Gerhard Dahl
Dec 15, 2010·International Journal of Molecular Sciences·Bin XueVladimir N Uversky
Mar 2, 2012·Biology of the Cell·Raf PonsaertsGeert Bultynck
Apr 26, 2012·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Federico Abascal, Rafael Zardoya
May 10, 2012·Nucleic Acids Research·Stephen R Bond, Christian C Naus
Jan 10, 2014·Nature·Byrappa VenkateshWesley C Warren
Jan 21, 2014·FEBS Letters·Juan ZouJenny J Yang
Aug 31, 2014·The Journal of Physiology·María C Hyzinski-GarcíaAlexander A Mongin
Nov 26, 2015·Pflügers Archiv : European journal of physiology·Zhongming MaJ Kevin Foskett
Apr 2, 2016·Nature Reviews. Molecular Cell Biology·Thomas J Jentsch
Oct 6, 2016·Biophysical Journal·Héctor Gaitán-PeñasRaúl Estévez
Dec 3, 2016·Nature Communications·Atsunori OshimaYoshinori Fujiyoshi
Aug 26, 2017·The Journal of Physiology·Antonella GradognaMichael Pusch
Dec 14, 2017·The Journal of General Physiology·Yu-Hsin ChiuDouglas A Bayliss

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Citations

Jan 18, 2019·The Journal of General Physiology·Kevin StrangeJerod S Denton
Jul 18, 2019·American Journal of Physiology. Renal Physiology·Venkatesh DeshpandeMark A Knepper
Dec 29, 2020·American Journal of Physiology. Cell Physiology·Toshiki YamadaKevin Strange
Apr 8, 2021·American Journal of Physiology. Cell Physiology·Eric E Figueroa, Jerod S Denton
Apr 19, 2021·Journal of Molecular Biology·Johanna SyrjanenHiro Furukawa
May 2, 2021·The Journal of Physiology·Hyehun ChoiFred S Lamb
Sep 2, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Corinne S WilsonAlexander A Mongin

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Methods Mentioned

BETA
PCR
transfection

Software Mentioned

s2D
PONDR
JPred
RaptorX
pClamp
Basic Local Alignment Search Tool

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