Chloride oscillation in pacemaker neurons regulates circadian rhythms through a chloride-sensing WNK kinase signaling cascade

Schellinger, Jeffrey N.; Sun, Qifei; Pleinis, John M.; An, Sung-Wan; Hu, Jianrui; Mercenne, Gaëlle; Titos, Iris; Huang, Chou‐Long; Rothenfluh, Adrian; Rodan, Aylin R.

doi:10.1016/j.cub.2022.03.017

Cited by 11 publications

(10 citation statements)

References 88 publications

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“…The WNK pathway generally inhibits KCCs and kcc knockdown thus could revert the Wnk knockdown effect. Although knockdown of kcc in the whole wing with a dsRNA construct that recapitulates kcc mutants [ 35 , 42 ] slightly decreased wing size, it did not modify the effect of Wnk D420A expression, suggesting that the effects of Wnk on wing size are not mediated by KCC ( S1C Fig ). Compartment size reduction is not an off-target effect of the Wnk RNAi, as it is fully rescued by overexpression of Drosophila Wnk and human WNK2 and partially rescued by mouse Wnk4 and rat Wnk1 ( Fig 3A–3F ; quantified in Fig 3G ).…”

Section: Resultsmentioning

confidence: 99%

Unanticipated domain requirements for Drosophila Wnk kinase in vivo

Yarikipati,

Jonusaite,

Pleinis

et al. 2023

PLoS Genet

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WNK (With no Lysine [K]) kinases have critical roles in the maintenance of ion homeostasis and the regulation of cell volume. Their overactivation leads to pseudohypoaldosteronism type II (Gordon syndrome) characterized by hyperkalemia and high blood pressure. More recently, WNK family members have been shown to be required for the development of the nervous system in mice, zebrafish, and flies, and the cardiovascular system of mice and fish. Furthermore, human WNK2 and Drosophila Wnk modulate canonical Wnt signaling. In addition to a well-conserved kinase domain, animal WNKs have a large, poorly conserved C-terminal domain whose function has been largely mysterious. In most but not all cases, WNKs bind and activate downstream kinases OSR1/SPAK, which in turn regulate the activity of various ion transporters and channels. Here, we show that Drosophila Wnk regulates Wnt signaling and cell size during the development of the wing in a manner dependent on Fray, the fly homolog of OSR1/SPAK. We show that the only canonical RF(X)V/I motif of Wnk, thought to be essential for WNK interactions with OSR1/SPAK, is required to interact with Fray in vitro. However, this motif is unexpectedly dispensable for Fray-dependent Wnk functions in vivo during fly development and fluid secretion in the Malpigian (renal) tubules. In contrast, a structure function analysis of Wnk revealed that the less-conserved C-terminus of Wnk, that recently has been shown to promote phase transitions in cell culture, is required for viability in vivo. Our data thus provide novel insights into unexpected in vivo roles of specific WNK domains.

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Section: Resultsmentioning

confidence: 99%

Unanticipated domain requirements for Drosophila Wnk kinase in vivo

Yarikipati,

Jonusaite,

Pleinis

et al. 2023

PLoS Genet

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“…Frontiers in Pharmacology frontiersin.org excitability (Zöllner and Stein, 2007;Trescot et al, 2008;Rocha et al, 2011;Huang et al, 2020). Animal studies have shown that the GABA neuronal response has a significant rhythm, and compared with ZT2, GABA neuronal reactivity at ZT6 is significantly lower (Wagner et al, 1997;Schellinger et al, 2022). In contrast, it can be speculated that GABA neuronal reactivity is stronger in the afternoon in humans.…”

Section: Morning Afternoon Pmentioning

confidence: 99%

Role of daytime variation in pharmaceutical effects of sufentanil, dezocine, and tramadol: A matched observational study

et al. 2022

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The role of daytime variation in the comprehensive pharmaceutical effects of commonly used opioid analgesics in clinical setting remains unclear. This study aimed to explore the differences in daytime variation among elective surgery patients who were scheduled to receive preemptive analgesia with equivalent doses of sufentanil, dezocine, and tramadol in the morning and afternoon. The analgesic effect was assessed by changes in the pressure pain threshold before and after intravenous administration of sufentanil, dezocine, and tramadol. Respiratory effects were evaluated using pulse oximetry, electrical impedance tomography, and arterial blood gas analysis. Other side effects, including nausea, sedation, and dizziness, were also recorded, and blood concentration was measured. The results showed that the analgesic effects of sufentanil, dezocine, and tramadol were significantly better in the morning than in afternoon. In the afternoon, sufentanil had a stronger sedative effect, whereas dezocine had a stronger inhibitory respiratory effect. The incidence of nausea was higher in the morning with tramadol. Additionally, significant differences in different side effects were observed among three opioids. Our results suggest that the clinical use of these three opioids necessitates the formulation of individualized treatment plans, accounting for different administration times, to achieve maximum analgesic effect with minimal side effects.

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“…Inarguably, the chloride (Cl – ) anion is an essential nutrient in physiology . Membrane-bound transporting proteins are resident on virtually every cell type, tuning chloride levels over a wide concentration range (3–110 mM) in extracellular, intracellular, and subcellular spaces. − Given this redundancy, the activity of chloride channels, exchangers, and transporters can be passive or controlled by a myriad of stimuli, including cations (e.g., Na + and Ca 2+ ), ligands (e.g., GABA and cAMP), or post-translational modifications. ,,,− In turn, chloride is linked to biological functions such as circadian rhythm, electrolyte balance, fluid secretion, and innate immunity. ,,− Indeed, disruptions in the activity, expression, and localization of chloride transporting proteins can lead to dysregulated chloride levels in disease states ranging from cancers, cardiac dysfunction, cystic fibrosis, kidney stones, and neurological disorders. − Across these contexts, the canonical view of chloride as a counterion is being reshaped. Recent evidence ascribes functional significance to chloride as a signaling ion that can allosterically regulate protein function and even control gene expression. ,,,− Thus, this indicates that cells can maintain and mobilize chloride from distinct pools.…”

Section: Introductionmentioning

confidence: 99%

“… 3 , 4 , 7 , 10 − 13 In turn, chloride is linked to biological functions such as circadian rhythm, electrolyte balance, fluid secretion, and innate immunity. 1 , 7 , 14 − 16 Indeed, disruptions in the activity, expression, and localization of chloride transporting proteins can lead to dysregulated chloride levels in disease states ranging from cancers, cardiac dysfunction, cystic fibrosis, kidney stones, and neurological disorders. 17 − 24 Across these contexts, the canonical view of chloride as a counterion is being reshaped.…”

Section: Introductionmentioning

confidence: 99%

Engineering the ChlorON Series: Turn-On Fluorescent Protein Sensors for Imaging Labile Chloride in Living Cells

Tutol,

Ong,

Phelps

et al. 2023

ACS Cent. Sci.

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Beyond its role as the "queen of electrolytes", chloride can also serve as an allosteric regulator or even a signaling ion. To illuminate this essential anion across such a spectrum of biological processes, researchers have relied on fluorescence imaging with genetically encoded sensors. In large part, these have been derived from the green fluorescent protein found in the jellyfish Aequorea victoria. However, a standalone sensor with a turn-on intensiometric response at physiological pH has yet to be reported. Here, we address this technology gap by building on our discovery of the anion-sensitive fluorescent protein mNeonGreen (mNG). The targeted engineering of two non-coordinating residues, namely K143 and R195, in the chloride binding pocket of mNG coupled with an anion walking screening and selection strategy resulted in the ChlorON sensors: ChlorON-1 (K143W/R195L), ChlorON-2 (K143R/R195I), and ChlorON-3 (K143R/R195L). In vitro spectroscopy revealed that all three sensors display a robust turn-on fluorescence response to chloride (20-to 45-fold) across a wide range of affinities (K d ≈ 30−285 mM). We further showcase how this unique sensing mechanism can be exploited to directly image labile chloride transport with spatial and temporal resolution in a cell model overexpressing the cystic fibrosis transmembrane conductance regulator. Building from this initial demonstration, we anticipate that the ChlorON technology will have broad utility, accelerating the path forward for fundamental and translational aspects of chloride biology.

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Chloride oscillation in pacemaker neurons regulates circadian rhythms through a chloride-sensing WNK kinase signaling cascade

Cited by 11 publications

References 88 publications

Unanticipated domain requirements for Drosophila Wnk kinase in vivo

Unanticipated domain requirements for Drosophila Wnk kinase in vivo

Role of daytime variation in pharmaceutical effects of sufentanil, dezocine, and tramadol: A matched observational study

Engineering the ChlorON Series: Turn-On Fluorescent Protein Sensors for Imaging Labile Chloride in Living Cells

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