Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2021.11.30.470531

Potassium effects on NCC are attenuated during inhibition of Cullin E3-ubiquitin ligases

Murali, S. K.·Little, R.·Poulsen, S. B.·Ferdaus, M.·Ellison, D. H.·McCormick, J. A.·Fenton, R. A.
View original source ↗Export metadata ↓

Abstract

The thiazide sensitive sodium-chloride co-transporter (NCC) plays a vital role in maintaining sodium (Na+) and potassium (K+) homeostasis. NCC activity is modulated by the with-no-lysine kinases 1 and 4 (WNK1 and WNK4), the abundance of which are controlled by the RING-type E3 ligase Cullin 3 (Cul3) and its substrate adapter Kelch-like protein 3. Dietary K+ intake has an inverse correlation with NCC activity, but the mechanism underlying this phenomenon remains to be fully elucidated. Here, we investigated the involvement of other members of the Cullin family in mediating K+ effects on NCC phosphorylation (active form) and abundance. In kidneys from mice fed diets varying in K+ content, there were negative correlations between NCC (phosphorylated and total) and active (neddylated) forms of Cullins (Cul1, 3, 4 and 5). High dietary K+ effects on phosphorylated NCC were attenuated in Cul3 mutant mice (CUL3-Het/{Delta}9). Short-term (30 min) and long-term (24 h) alterations in the extracellular K+ concentration did not affect Cullin neddylation levels in ex vivo renal tubules. Short-term, the ability of high extracellular K+ to decrease NCC phosphorylation was preserved in the presence of MLN4924 (pan Cullin inhibitor), but the response to low extracellular K+ was absent. Long-term, MLN4924 attenuated the effects of high extracellular K+ on NCC phosphorylation and responses to low extracellular K+ were absent. Our data suggest that in addition to Cul3, other Cullins are involved in mediating the effects of K+ on NCC phosphorylation and abundance.

Source connections

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Murali, S. K., Little, R., Poulsen, S. B., Ferdaus, M., Ellison, D. H., McCormick, J. A., Fenton, R. A.. 2021-12-01. Potassium effects on NCC are attenuated during inhibition of Cullin E3-ubiquitin ligases. https://doi.org/10.1101/2021.11.30.470531

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Trunk muscle activity across various trunk-limb coordination patterns in centipede locomotion

Animals coordinate movements of their limbs and flexible bodies, yet how trunk muscle activity changes across locomotor patterns remains unclear. We simultaneously recorded electromyograms from trunk muscles (deep dorsal oblique muscles) and trunk-limb kinematics in two centipede species exhibiting retrograde and direct locomotor waves during swimming and walking. During swimming, trunk muscle activity followed a similar phase relationship with trunk bending in both species despite opposite wave directions and different involvement of limbs, suggesting common active generation of undulation. During fast walking, trunk muscle activity was strongest around the ipsilateral swing phase in the undulatory retrograde-wave gait of Scolopendra mutilans, but weaker and associated with the ipsilateral stance phase despite the nearly straight trunk in the direct-wave gait of Scolopocryptops rubiginosus. Together, our findings suggest that the same trunk muscles serve two contrasting mechanical roles depending on locomotor mode: either generating trunk undulation or actively straightening the trunk against limb-induced deformation.

physiology↗
bioRxiv2026

Quantifying and Visualizing the Invisible Hazard of Infant Rebreathing

BACKGROUND: Rebreathing of expired gases during prone infant sleeping contributes to hypoxic and hypercapnic exposure, even without airway obstruction. We investigated how anatomical, physiological, and environmental factors influence aerodynamic rebreathing. METHODS: A dynamically scaled in vitro model simulated prone nasal breathing corresponding to infants weighing 2 to 5 kg, with nostril diameters of 3.2 to 6.0 mm and breathing frequencies of 25 to 40 breaths/min. Ambient temperature and sleep-surface characteristics were varied. Rebreathing was quantified using tracer measurements, while flow visualization revealed the underlying aerodynamic mechanisms. RESULTS: Rebreathing exceeded 60% despite unobstructed nasal openings. Increasing ambient temperature from 23 to 30 degrees C increased rebreathing by 68 to 77%, while reducing simulated infant mass from 5 to 2 kg increased rebreathing by 39 to 46%. Fibrous surfaces increased rebreathing, particularly near inclined nasal openings. A novel finding was that increasing nostril diameter from 3.2 to 6.0 mm increased rebreathing by up to 50%. Flow visualization revealed vortical structures that retained expired fluid near the nasal openings, facilitating re-inspiration. CONCLUSIONS: Aerodynamic rebreathing depends strongly on simulated infant characteristics and sleeping environments. These findings are consistent with established safe-sleep recommendations and identify nostril diameter, for the first time, as a potentially important anatomical factor warranting clinical investigation.

physiology↗
bioRxiv2026

Epigenetic Rescue of Disuse Muscle Atrophy by Histone Deacetylase Inhibitor Trichostatin A

Mechanical unloading rapidly induces skeletal muscle atrophy and functional deterioration, yet how the loss of mechanical input influences nuclear architecture, chromatin organization, and associated transcriptional programs remains poorly understood. Here, we investigated whether pharmacological inhibition of histone deacetylases (HDACs) using Trichostatin A (TSA) could attenuate the consequences of continued mechanical unloading in a murine hindlimb suspension model. Following 14 days of unloading, mice exhibited impaired locomotor activity, altered muscle architecture, and widespread transcriptional reprogramming characterized by increased expression of atrophy associated genes, inflammatory mediators, and extracellular matrix remodeling pathways, alongside suppression of mitochondrial metabolic programs. Super resolution imaging further revealed irregular Lamin A/C organization and disruption of discrete H3K9me3 associated heterochromatin foci. Systemic TSA treatment significantly attenuated the decline in locomotor activity, accompanied by trends toward reduced body weight loss, and preservation of muscle morphology. Transcriptomic analysis demonstrated a substantial shift toward the baseline expression profile, with high-dose TSA attenuating FOXO associated catabolic programs, inflammatory, and extracellular matrix-related signatures, while enhancing mitochondrial oxidative phosphorylation pathways. Quantitative gene level and pathway analyses further revealed dose dependent and selective reversal of unloading associated transcriptional changes. Notably, TSA treatment also partially preserved nuclear lamina organization and the focal distribution of H3K9me3 associated heterochromatin. Despite these muscle specific benefits, TSA did not prevent trabecular bone loss over the 14-day unloading period, although several muscle-expressed genes potentially involved in muscle to bone communication were altered by treatment. Together, these findings demonstrate that HDAC inhibition counteracts multiple functional and molecular consequences of skeletal muscle unloading and is associated with partial preservation of nuclear and heterochromatin organization. This study supports a link between mechanical unloading, nuclear architectural remodeling, and HDAC sensitive transcriptional regulation, providing a foundation for epigenetic strategies to counter disuse induced muscle deterioration.

physiology↗