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

Abstract

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.

Loss of Slc12a2 specifically in pancreatic β-cells drives metabolic syndrome in mice

“…Therefore, the physiological metabolic consequences of losing Nkcc1 in β-cells are potentially related to reduced β-cell mass/volume/size due to dysregulated [Cl – ] i , altered Cl − channel-mediated electrical activity or a combination of both. In fact, inhibition of β-cell Nkcc1 reduced glucose-induced β-cell electrical oscillations modulated by Cl − channels [ 29 , 31 ] whereas isovolumetric circadian oscillations in [Cl – ] i , determined by the activity of Nkcc1 / Kcc , established the frequency of action potential firings in electrically excitable cells [ 95 ]. Regardless of the underlying mechanisms, the age-related metabolic consequences of altered pulsatile/circadian insulin release are multiple [ 16 ].…”

Pacemaker translocations and power laws in 2D stem cell-derived cardiomyocyte cultures

“…Microelectrode arrays were used to record cardiomyocyte local field potentials (hereafter called field potentials), which are extracellular electrical signals generated in part by transient imbalances in ion concentrations in the intercellular space [ 57 – 59 ]. These field potentials resemble, but are not equivalent to, electrocardiogram recordings, preventing analysis of P, Q, and S waves.…”

Control of circadian rhythm on cortical excitability and synaptic plasticity

“…The increased excitability at night can be countered by bumetanide, an inhibitor of the cotransporter NKCC1 that import Cl – in neurons. Although neither studies demonstrated that the observed diurnal change of intracellular Cl – is directly linked to the circadian clock, it is tempting to speculate that the observed changes are, at least to a certain extent, due to the same mechanisms observed in cardiomyocytes ( Stangherlin et al, 2021 ). These data might contribute to explain the dependency of LTP on the time of the day.…”

“…This mechanism is suggested by a manifestation of circadian biology that has been known for several years but it has not permeated the neurobiology community yet: during the circadian cycle the intracellular concentration of Na + , K + , Cl − , and Mg 2+ oscillates in phase (Feeney et al, 2016;O'Neill et al, 2020). This process was demonstrated first in non-excitable cells, until a recent beautiful study has demonstrated that the circadian clock causes a periodic change of intracellular K + , Na + and Cl − in cardiomyocytes (Stangherlin et al, 2021). As expected, this process influences cells excitability leading to a diurnal cycle of the frequency of the spontaneous heartbeat that accelerates in correspondence of elevated intracellular Na + and K + .…”

“…As expected, this process influences cells excitability leading to a diurnal cycle of the frequency of the spontaneous heartbeat that accelerates in correspondence of elevated intracellular Na + and K + . The periodic changes in intracellular ion concentration are controlled by ion cotransporters and this is driven by the cyclic circadian activation of mTOR so that high ion concentration occurs in correspondence of low mTOR activity ( Stangherlin et al, 2021 ). Importantly, flattening mTOR activity by its pharmacological inhibition cancels the circadian rhythm of heartbeat frequency.…”