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

Alessandra Stangherlin, Silvia Barbiero, Aiwei Zeng, Estere Seinkmane, Sew Peak Chew, Andrew D Beale, Edward A Hayter, Alina Guna, Alison J Inglis, Marrit Putker, Eline Bartolami, Stefan Matile, Nicolas Lequeux, Thomas Pons, Jason Day, Gerben van Ooijen, Rebecca M Voorhees, David A Bechtold, Emmanuel Derivery, Rachel S EdgarPeter Newham, John S O'Neill

Research output: Contribution to journalArticlepeer-review


Between 6-20% of the cellular proteome is under circadian control and tunes mammalian cell function with daily environmental cycles. For cell viability, and to maintain volume within narrow limits, the daily variation in osmotic potential exerted by changes in the soluble proteome must be counterbalanced. The mechanisms and consequences of this osmotic compensation have not been investigated before. In cultured cells and in tissue we find that compensation involves 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 confer daily variation in electrical activity. 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.

Original languageEnglish
Article number6035
JournalNature Communications
Issue number1
Publication statusPublished - 15 Oct 2021


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