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dc.contributor.authorAdragna, Norma C.en_US
dc.contributor.authorRavilla, Nagendra B.en_US
dc.contributor.authorLauf, Peter K.en_US
dc.contributor.authorBegum, Gulnazen_US
dc.contributor.authorKhanna, Arjun R.en_US
dc.contributor.authorSun, Dandanen_US
dc.contributor.authorKahle, Kristopher T.en_US
dc.date.accessioned2015-08-03T14:01:30Z
dc.date.issued2015en_US
dc.identifier.citationAdragna, Norma C., Nagendra B. Ravilla, Peter K. Lauf, Gulnaz Begum, Arjun R. Khanna, Dandan Sun, and Kristopher T. Kahle. 2015. “Regulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasis.” Frontiers in Cellular Neuroscience 9 (1): 255. doi:10.3389/fncel.2015.00255. http://dx.doi.org/10.3389/fncel.2015.00255.en
dc.identifier.issn1662-5102en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17820780
dc.description.abstractThe defense of cell volume against excessive shrinkage or swelling is a requirement for cell function and organismal survival. Cell swelling triggers a coordinated homeostatic response termed regulatory volume decrease (RVD), resulting in K+ and Cl− efflux via activation of K+ channels, volume-regulated anion channels (VRACs), and the K+-Cl− cotransporters, including KCC3. Here, we show genetic alanine (Ala) substitution at threonines (Thr) 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-regulates KCC3a activity up to 25-fold in normally inhibitory isotonic conditions, but is also accompanied by reversal of activity of the related bumetanide-sensitive Na+-K+-2Cl− cotransporter isoform 1 (NKCC1). This results in a rapid (<10 min) and significant (>90%) reduction in intracellular K+ content (Ki) via both Cl-dependent (KCC3a + NKCC1) and Cl-independent [DCPIB (VRAC inhibitor)-sensitive] pathways, which collectively renders cells less prone to acute swelling in hypotonic osmotic stress. Together, these data demonstrate the phosphorylation state of Thr991/Thr1048 in KCC3a encodes a potent switch of transporter activity, Ki homeostasis, and cell volume regulation, and reveal novel observations into the functional interaction among ion transport molecules involved in RVD.en
dc.language.isoen_USen
dc.publisherFrontiers Media S.A.en
dc.relation.isversionofdoi:10.3389/fncel.2015.00255en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496573/pdf/en
dash.licenseLAAen_US
dc.subjectK-Cl cotransportersen
dc.subjectKCC3en
dc.subjectNKCC1en
dc.subjectSPAKen
dc.subjectcell volume homeostasisen
dc.subjectregulatory volume decreaseen
dc.subjectcerebral edemaen
dc.subjectneurodegenerationen
dc.titleRegulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasisen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalFrontiers in Cellular Neuroscienceen
dash.depositing.authorKhanna, Arjun R.en_US
dc.date.available2015-08-03T14:01:30Z
dc.identifier.doi10.3389/fncel.2015.00255*
dash.contributor.affiliatedKhanna, Arjun
dash.contributor.affiliatedKahle, Kristopher T.


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