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Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

Stangherlin, Alessandra and Wong, David C. S. and Barbiero, Silvia and Watson, Joseph L. and Zeng, Aiwei and Seinkmane, Estere and Chew, Sew Peak and Beale, Andrew D. and Hayter, Edward A. and Guna, Alina and Inglis, Alison J. and Bartolami, Eline and Matile, Stefan and Lequeux, Nicolas and Pons, Thomas and Day, Jason and van Ooijen, Gerben and Voorhees, Rebecca M. and Bechtold, David A. and Derivery, Emmanuel and Edgar, Rachel S. and Newham, Peter and O'Neill, John S. (2020) Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology. . (Unpublished)

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Between 6-20% of the cellular proteome is under circadian control to tune cell function with cycles of environmental change. For cell viability, and to maintain volume within narrow limits, the osmotic pressure exerted by changes in the soluble proteome must be compensated. The mechanisms and consequences underlying compensation are not known. Here, we show in cultured mammalian cells and in vivo that compensation requires electroneutral active transport of Na⁺, K⁺, and Cl⁻ through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes alter their electrical activity at different times of the day. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Guna, Alina0000-0003-0757-1255
Inglis, Alison J.0000-0002-9008-8565
Voorhees, Rebecca M.0000-0003-1640-2293
O'Neill, John S.0000-0003-2204-6096
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Posted May 28, 2020. We thank Alex Harmer, Helen Causton, and past and present O’Neill lab members for valuable discussion and contribution, particularly Priya Crosby and Ned Hoyle, visual aids, and the biological services group for assistance with animal work and husbandry. E.D. was supported by the Medical Research Council (MC_UP_1201/13) and the Human Frontier Science Program (CDA00034/2017-C); RSE by a Wellcome Trust Sir Henry Dale Fellowship (208790/Z/17/Z). This work was supported by the AstraZeneca Blue Skies Initiative and the Medical Research Council (MC_UP_1201/4). Author contributions: J.S.O., P.N., R.S.E. and A.S. conceived the idea and wrote the manuscript. E.B and S.M. synthesised the cell penetrating poly(disulphide)s, T.P. and N.P. synthesised quantum dots. A.S., D.W., S.B., J.W., A.Z., E.S., S.P.C., A.B., E.H., A.G, A. I., J.D., R.V., D.B., E.D. and R.S.E. performed experiments and analysis, G.v.O. made pivotal intellectual contributions. Competing interests: P.N. holds shares in AstraZeneca. The other authors declare no competing interests. Data and materials availability: All data is available in the main text or the supplementary materials. Codes for quantum dot tracking and analysis will be available on request.
Funding AgencyGrant Number
Medical Research Council (UK)MC_UP_1201/13
Human Frontier Science ProgramCDA00034/2017-C
Wellcome Trust208790/Z/17/Z
AstraZeneca Blue Skies InitiativeUNSPECIFIED
Medical Research Council (UK)MC_UP_1201/4
Record Number:CaltechAUTHORS:20200528-134326798
Persistent URL:
Official Citation:Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology. Alessandra Stangherlin, David C.S. Wong, Silvia Barbiero, Joseph L Watson, Aiwei Zeng, Estere Seinkmane, Sew P Chew, Andrew D Beale, Edward A Hayter, Alina Guna, Alison Inglis, Eline Bartolami, Stefan Matile, Nicolas Lequeux, Thomas Pons, Jason Day, Gerben van Ooijen, Rebecca M Voorhees, David Bechtold, Emmanuel Derivery, Rachel S Edgar, Peter Newham, John S O'Neill. bioRxiv 2020.05.28.118398; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103524
Deposited By: Tony Diaz
Deposited On:28 May 2020 22:02
Last Modified:23 Jun 2020 22:49

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