Journal article
Chloride oscillation in pacemaker neurons regulates circadian rhythms through a chloride-sensing WNK kinase signaling cascade
Current biology, Vol.32(6), pp.1429-1438.e6
03/28/2022
DOI: 10.1016/j.cub.2022.03.017
PMCID: PMC8972083
PMID: 35303418
Abstract
Central pacemaker neurons regulate circadian rhythms and undergo diurnal variation in electrical activity in mammals and flies.(1,2) Circadian variation in the intracellular chloride concentration of mammalian pacemaker neurons has been proposed to influence the response to GABAergic neurotransmission through GABA(A) receptor chloride channels.(3) However, results have been contradictory,(4-9) and a recent study demonstrated circadian variation in pacemaker neuron chloride without an effect on GABA response.(10) Therefore, whether and how intracellular chloride regulates circadian rhythms remains controversial. Here, we demonstrate a signaling role for intracellular chloride in the Drosophila small ventral lateral (sLN(v)) pacemaker neurons. In control flies, intracellular chloride increases in sLN(v)s over the course of the morning. Chloride transport through sodium-potassium-2-chloride (NKCC) and potassium-chloride (KCC) cotransporters is a major determinant of intracellular chloride concentrations.(11) Drosophila melanogaster with loss-of-function mutations in the NKCC encoded by Ncc69 have abnormally low intracellular chloride 6 h after lights on, loss of morning anticipation, and a prolonged circadian period. Loss of kcc, which is expected to increase intracellular chloride, suppresses the long-period phenotype of Ncc69 mutant flies. Activation of a chloride-inhibited kinase cascade, consisting of WNK (with no lysine [K]) kinase and its downstream substrate, Fray, is necessary and sufficient to prolong period length. Fray activation of an inwardly rectifying potassium channel, Irk1, is also required for the long-period phenotype. These results indicate that the NKCC-dependent rise in intracellular chloride in Drosophila sLN(v) pacemakers restrains WNK-Fray signaling and overactivation of an inwardly rectifying potassium channel to maintain normal circadian period length.
Details
- Title: Subtitle
- Chloride oscillation in pacemaker neurons regulates circadian rhythms through a chloride-sensing WNK kinase signaling cascade
- Creators
- Jeffrey N. Schellinger - The University of Texas Southwestern Medical CenterQifei Sun - The University of Texas Southwestern Medical CenterJohn M. Pleinis - University of UtahSung-Wan An - University of IowaJianrui Hu - University of UtahGaelle Mercenne - University of UtahIris Titos - University of UtahChou-Long Huang - University of IowaAdrian Rothenfluh - University of UtahAylin R. Rodan - University of Utah
- Resource Type
- Journal article
- Publication Details
- Current biology, Vol.32(6), pp.1429-1438.e6
- Publisher
- Elsevier
- DOI
- 10.1016/j.cub.2022.03.017
- PMID
- 35303418
- PMCID
- PMC8972083
- ISSN
- 0960-9822
- eISSN
- 1879-0445
- Number of pages
- 16
- Grant note
- DK091316; DK106350; DK110358; DK111542; AA019526; AA026818; DA049635 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 2P40OD010949 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA NIH P40OD018537 / Bloomington Drosophila Stock Center
- Language
- English
- Date published
- 03/28/2022
- Academic Unit
- Nephrology; Internal Medicine
- Record Identifier
- 9984359789302771
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