1. 2019
Huang H, Song S, Banerjee S, Jiang T, Zhang J, Kahle KT, Sun D, Zhang Z.
Aging Dis. 2019 Jun 1;10(3):626-636. doi: 10.14336/AD.2018.0928. eCollection 2019 Jun. Review.
In recent years, cation-chloride
cotransporters (CCCs) have drawn attention in the medical neuroscience
research. CCCs include the family of Na+-coupled Cl- importers (NCC, NKCC1, and NKCC2), K+-coupled Cl-
exporters (KCCs), and possibly polyamine transporters (CCC9) and CCC
interacting protein (CIP1). For decades, CCCs have been the targets of
several commonly used diuretic drugs, including hydrochlorothiazide,
furosemide, and bumetanide. Genetic mutations of NCC and NKCC2 cause
congenital renal tubular disorders and lead to renal salt-losing
hypotension, secondary hyperreninemia, and hypokalemic metabolic
alkalosis. New studies reveal that CCCs along with their regulatory WNK
(Kinase with no lysine (K)), and SPAK (Ste20-related
proline-alanine-rich kinase)/OSR1(oxidative stress-responsive kinase-1)
are essential for regulating cell volume and maintaining ionic
homeostasis in the nervous system, especially roles of the WNK-SPAK-NKCC1 signaling pathway in ischemic brain injury and hypersecretion of cerebrospinal fluid in post-hemorrhagic hydrocephalus. In addition, disruption of Cl-
exporter KCC2 has an effect on synaptic inhibition, which may be
involved in developing pain, epilepsy, and possibly some
neuropsychiatric disorders. Interference with KCC3 leads to peripheral
nervous system neuropathy as well as axon and nerve fiber swelling and
psychosis. The WNK-SPAK/OSR1-CCCs
complex emerges as therapeutic targets for multiple neurological
diseases. This review will highlight these new findings.
KEYWORDS:
KCCs; NKCC1; WNK-SPAK/OSR1; brain edema; cell volume regulation; ischemic stroke
KCCs; NKCC1; WNK-SPAK/OSR1; brain edema; cell volume regulation; ischemic stroke
PMID:31165006PMCID:PMC653821DOI:10.14336/AD.2018.0928
Free PMC Article
2. 2018
Kim MJ, Yang HJ, Kim Y, Kang I, Kim SS, Cho YW.
Neuropharmacology. 2018 Jun;135:355-367. doi: 10.1016/j.neuropharm.2018.03.035. Epub 2018 Mar 27.
Serotonergic neurons in the dorsal
raphe nucleus (DRN) act as wake-inducing neurons in the sleep-wake cycle
and are controlled by gamma-aminobutyric acid (GABA) synaptic inputs.
We investigated daily changes in GABAergic inhibition of the rat DRN
neurons and the role of nitric oxide (NO) and cation-chloride
co-transporters in the GABAergic action. Neuronal NO synthase (nNOS) was
co-expressed in 74% of serotonergic DRN neurons and nNOS expression was
higher during daytime (the sleep cycle) than that during nighttime (the
wake cycle). GABAergic hyperpolarization of DRN neurons produced by
GABAA receptor agonist muscimol was greater and the
equilibrium potential of muscimol showed a hyperpolarizing shift during
daytime compared to that during nighttime. Expression levels of
potassium-chloride co-transporter 2 (KCC2) were higher during daytime
than that during nighttime, whereas there were no changes in
sodium-potassium-chloride co-transporter 1 (NKCC1) expression.
With-no-lysine kinase (WNK)
isoform 1 was more highly expressed during daytime than that during
nighttime. Total Ste20-related proline alanine rich kinase (SPAK) and
oxidative stress response kinase 1 (OSR1) were also higher during
daytime than during nighttime, while there were no changes in
phosphorylated SPAK and OSR1. Consistent with the findings during the
sleep-wake cycle, ex vivo treatment of DRN slices with a NO donor sodium
nitroprusside (SNP) increased the expression of KCC2, WNK1, WNK2, WNK3,
SPAK, and OSR1, whilst decreasing phosphorylated SPAK. These results
suggest that GABAergic synaptic inhibition of DRN serotonergic neurons
shows daily changes during the sleep-wake cycle, which might be
regulated by daily changes in nNOS-derived NO and WNK-SPAK/OSR1-KCC2 signaling.
Copyright © 2018 Elsevier Ltd. All rights reserved.
KEYWORDS:
Dorsal raphe nucleus; Gamma-aminobutyric acid; Nitric oxide; Potassium-chloride cotransporter; Serotonin; Sleep-wake cycle
Dorsal raphe nucleus; Gamma-aminobutyric acid; Nitric oxide; Potassium-chloride cotransporter; Serotonin; Sleep-wake cycle
3.2018
Chung WY, Han JW, Heo W, Lee MG, Kim JY.
Mol Cell Biochem. 2018 Oct;447(1-2):165-174. doi: 10.1007/s11010-018-3301-4. Epub 2018 Feb 1.
"With no lysine" (WNK) kinases have been shown to regulate various ion transporters in various tissues, but studies on the function of WNK kinases in the brain
have been limited. In this study, we discovered that WNK1 and WNK4 in
POMC-expressing neuronal cells in WNK1 overexpressed transgenic mice
(WNK1 TG) decrease appetite via degradation of Kir6.2. Weight gain after
20 weeks of age was delayed in WNK1 TG mice as a result of reduced food
intake. Expression of WNK1 and proopiomelanocortin (POMC) was higher in
POMC-expressing neurons in the hypothalamus of WNK1 TG mice than in WT
mice. Immunostaining of serial sections of the hypothalamus revealed
that POMC-expressing neurons were smaller in WNK1 TG mice than in WT
mice. In addition, expression of Kir6.2 was significantly reduced in
WNK1 TG mice. Overexpression and knockdown of WNK4 demonstrated that
WNK4 regulates protein expression of Kir6.2 via protein-protein
interaction. Accordingly, reduced age-dependent weight gain of WNK1 TG
mice seems to be related with the decreased Kir6.2 expression via WNK1-
and WNK4-regulated protein stability of Kir6.2.
KEYWORDS:
Appetite; Kir6.2; POMC-expressing neuron; Protein degradation; Transgenic mice; WNK1; WNK4
Appetite; Kir6.2; POMC-expressing neuron; Protein degradation; Transgenic mice; WNK1; WNK4
4. 2019
Wilson CS, Mongin AA.
Neurosci Lett. 2019 Jan 10;689:33-44. doi: 10.1016/j.neulet.2018.01.012. Epub 2018 Jan 9. Review.
It is well known that the electrical signaling in neuronal networks is modulated by chloride (Cl-) fluxes via the inhibitory GABAA and glycine receptors. Here, we discuss the putative contribution of Cl- fluxes and intracellular Cl-
to other forms of information transfer in the CNS, namely the
bidirectional communication between neurons and astrocytes. The
manuscript (i) summarizes the generic functions of Cl- in cellular physiology, (ii) recaps molecular identities and properties of Cl- transporters and channels in neurons and astrocytes, and (iii) analyzes emerging studies implicating Cl- in the modulation of neuroglial communication.
The existing literature suggests that neurons can alter astrocytic Cl- levels in a number of ways; via (a) the release of neurotransmitters and activation of glial transporters that have intrinsic Cl- conductance,
(b) the metabotropic receptor-driven changes in activity of the electroneutral cation-Cl- cotransporter NKCC1, and (c) the transient, activity-dependent changes in glial cell volume which open the volume-regulated Cl-/anion channel VRAC. Reciprocally, astrocytes are thought to alter neuronal [Cl-]i through either (a) VRAC-mediated release of the inhibitory gliotransmitters, GABA and taurine, which open neuronal GABAA and glycine receptor/Cl- channels, or (b) the gliotransmitter-driven stimulation of NKCC1. The most important recent developments in this area are the identification of the molecular composition and functional heterogeneity of brain VRAC channels, and the discovery of a new cytosolic [Cl-] sensor - the Wnk family protein kinases. With new work in the field, our understanding of the role of Cl- in information processing within the CNS is expected to be significantly updated.
The existing literature suggests that neurons can alter astrocytic Cl- levels in a number of ways; via (a) the release of neurotransmitters and activation of glial transporters that have intrinsic Cl- conductance,
(b) the metabotropic receptor-driven changes in activity of the electroneutral cation-Cl- cotransporter NKCC1, and (c) the transient, activity-dependent changes in glial cell volume which open the volume-regulated Cl-/anion channel VRAC. Reciprocally, astrocytes are thought to alter neuronal [Cl-]i through either (a) VRAC-mediated release of the inhibitory gliotransmitters, GABA and taurine, which open neuronal GABAA and glycine receptor/Cl- channels, or (b) the gliotransmitter-driven stimulation of NKCC1. The most important recent developments in this area are the identification of the molecular composition and functional heterogeneity of brain VRAC channels, and the discovery of a new cytosolic [Cl-] sensor - the Wnk family protein kinases. With new work in the field, our understanding of the role of Cl- in information processing within the CNS is expected to be significantly updated.
Copyright © 2018 Elsevier B.V. All rights reserved.
KEYWORDS:
Chloride channels; Chloride homeostasis; KCC; NKCC; Neuron-astrocyte communication; VRAC; WNK
Chloride channels; Chloride homeostasis; KCC; NKCC; Neuron-astrocyte communication; VRAC; WNK
5. 2017
Heubl
M, Zhang J, Pressey JC, Al Awabdh S, Renner M, Gomez-Castro F, Moutkine
I, Eugène E, Russeau M, Kahle KT, Poncer JC, Lévi S.
Nat Commun. 2017 Nov 24;8(1):1776. doi: 10.1038/s41467-017-01749-0.
The K+-Cl- co-transporter KCC2 (SLC12A5) tunes the efficacy of GABAA receptor-mediated transmission by regulating the intraneuronal chloride concentration [Cl-]i.
KCC2 undergoes activity-dependent regulation in both physiological and
pathological conditions. The regulation of KCC2 by synaptic excitation
is well documented; however, whether the transporter is regulated by
synaptic inhibition is unknown. Here we report a mechanism of KCC2
regulation by GABAA receptor (GABAAR)-mediated transmission in mature hippocampal neurons. Enhancing GABAAR-mediated
inhibition confines KCC2 to the plasma membrane, while antagonizing
inhibition reduces KCC2 surface expression by increasing the lateral
diffusion and endocytosis of the transporter. This mechanism utilizes Cl- as an intracellular secondary messenger and is dependent on phosphorylation of KCC2 at threonines 906 and 1007 by the Cl--sensing
kinase WNK1. We propose this mechanism contributes to the homeostasis
of synaptic inhibition by rapidly adjusting neuronal [Cl-]i to GABAAR activity.PMID:29176664PMCID:PMC5701213DOI:10.1038/s41467-017-01749-0
Free PMC Article
6.
Vibhuti, Khan R, Sharma A, Jain S, Mohanty S, Prasad K.
J Neurochem. 2017 Dec;143(6):722-735. doi: 10.1111/jnc.14241. Epub 2017 Dec 4. Retraction in: J Neurochem. 2018 Jun;145(6):516.
7.
Sasaki
E, Susa K, Mori T, Isobe K, Araki Y, Inoue Y, Yoshizaki Y, Ando F, Mori
Y, Mandai S, Zeniya M, Takahashi D, Nomura N, Rai T, Uchida S, Sohara
E.
Mol Cell Biol. 2017 Mar 17;37(7). pii: e00508-16. doi: 10.1128/MCB.00508-16. Print 2017 Apr 1.
- PMID:
- 28052936
8.
Delpire E, Kahle KT.
Expert Opin Ther Targets. 2017 Feb;21(2):113-116. doi: 10.1080/14728222.2017.1275569. Epub 2017 Jan 5. No abstract available.
- PMID:
- 28019725
9.2017
Bhuiyan MIH, Song S, Yuan H, Begum G, Kofler J, Kahle KT, Yang SS, Lin SH, Alper SL, Subramanya AR, Sun D.
J Cereb Blood Flow Metab. 2017 Aug;37(8):2780-2794. doi: 10.1177/0271678X16675368. Epub 2016 Jan 1.
With-no-lysine kinase (WNK) and Na+-K+-2Cl- cotransporter 1 (NKCC1) are involved in the pathogenesis of hypertension. In this study, we investigated the WNK-NKCC1
signaling pathway in spontaneously hypertensive rats (SHR) and their
associated susceptibility to stroke injury. Basal NKCC1 protein levels
were higher in SHR than in normotensive Wistar Kyoto (WKY) rat brains.
After inducing ischemic stroke, adult male WKY and SHR received either
saline or NKCC1 inhibitor bumetanide (10 mg/kg/day, i.p.) starting at
3-h post-reperfusion. NKCC1 inhibition blunted the extent of ischemic
infarction in SHR and improved their neurobehavioral functions.
Interestingly, ischemia led to increased NKCC1 phosphorylation in SHR
but not in WKY rats. Pronounced elevation of WNK1, WNK2 and WNK4 protein
and downregulation of WNK3 were detected in ischemic SHR, but not in
ischemic WKY rats. Upregulation of WNK-NKCC1 complex in ischemic SHR brain was associated with increased Ca2+-binding
protein 39 (Cab39), without increases in Ste20-related proline
alanine-rich kinase or oxidative stress-responsive kinase-1. Moreover,
subacute middle cerebral artery stroke human brain autopsy exhibited increased expression of NKCC1 protein. We conclude that augmented WNK-Cab39-NKCC1 signaling in SHR is associated with an increased susceptibility to ischemic brain damage and may serve as a novel target for anti-hypertensive and anti-ischemic stroke therapy.KEYWORDS:
Bumetanide; Cab39; NKCC1; SHR; WNK kinase; hypertension; ischemic strokePMID:27798271 PMCID: PMC5536788 DOI: 10.1177/0271678X16675368 [Indexed for MEDLINE]
10. 2016
Tang BL.
Brain Res Bull. 2016 Jul;125:92-8. doi: 10.1016/j.brainresbull.2016.04.017. Epub 2016 Apr 27. Review.
Members of With-no-lysine (WNK)
family of serine-threonine kinase are key regulators of chloride ion
transport in diverse cell types, controlling the activity and the
surface expression of cation-chloride (Na(+)/K(+)-Cl(-))
co-transporters. Mutations in WNK1 and WNK4 are linked to a hereditary
form of hypertension, and WNKs have been extensively investigated
pertaining to their roles in renal epithelial ion homeostasis. However,
some members of the WNK family and their splice isoforms are also expressed in the mammalian brain,
and have been implicated in aspects of hereditary neuropathy as well as
neuronal and glial survival. WNK2, which is exclusively enriched in
neurons, is well known as an anti-proliferative tumor suppressor. WNK3,
on the other hand, appears to promote cell survival as its inhibition
enhances neuronal apoptosis. However, loss of WNK3 has been recently
shown to reduce ischemia-associated brain
damage. In this review, I surveyed the potentially context-dependent
roles of WNKs in neurological disorders and neuronal survival.
Copyright © 2016 Elsevier Inc. All rights reserved.KEYWORDS:
K(+)-Cl(−)co-transporter
2 (KCC2); Na(+)/K(+)-Cl(−) cotransporter 1 (NKCC1); Neuronal death;
Tumor suppressor; With-no-lysine(K) (WNK) kinase
11.
Zhao
H, Nepomuceno R, Gao X, Foley LM, Wang S, Begum G, Zhu W, Pigott VM,
Falgoust LM, Kahle KT, Yang SS, Lin SH, Alper SL, Hitchens TK, Hu S,
Zhang Z, Sun D.
J Cereb Blood Flow Metab. 2017 Feb;37(2):550-563. doi: 10.1177/0271678X16631561. Epub 2016 Jul 20.
- PMID:
- 26861815
12.
Watanabe M, Fukuda A.
Front Cell Neurosci. 2015 Sep 24;9:371. doi: 10.3389/fncel.2015.00371. eCollection 2015. Review.
- PMID:
- 26441542
13.
Kahle KT, Khanna AR, Alper SL, Adragna NC, Lauf PK, Sun D, Delpire E.
Trends Mol Med. 2015 Aug;21(8):513-23. doi: 10.1016/j.molmed.2015.05.008. Epub 2015 Jul 1. Review.
- PMID:
- 26142773
14.
Friedel P, Kahle KT, Zhang J, Hertz N, Pisella LI, Buhler E, Schaller F, Duan J, Khanna AR, Bishop PN, Shokat KM, Medina I.
Sci Signal. 2015 Jun 30;8(383):ra65. doi: 10.1126/scisignal.aaa0354.
- PMID:
- 26126716
15. 2015
Borrás J, Salker MS, Elvira B, Warsi J, Fezai M, Hoseinzadeh Z, Lang F.
Nephron. 2015;130(3):221-8. doi: 10.1159/000433567. Epub 2015 Jun 25.
BACKGROUND/AIMS:Kinases involved in the regulation of epithelial transport include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1). SPAK and OSR1 are both regulated by WNK (with-no-K(Lys)) kinases. The present study explored whether SPAK and/or OSR1 influence the excitatory amino acid transporter EAAT3, which accomplishes glutamate and aspartate transport in kidney, intestine and brain. METHODS:
BACKGROUND/AIMS:Kinases involved in the regulation of epithelial transport include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1). SPAK and OSR1 are both regulated by WNK (with-no-K(Lys)) kinases. The present study explored whether SPAK and/or OSR1 influence the excitatory amino acid transporter EAAT3, which accomplishes glutamate and aspartate transport in kidney, intestine and brain. METHODS:
cRNA
encoding EAAT3 was injected into Xenopus laevis oocytes with or without
additional injection of cRNA encoding wild-type SPAK, constitutively
active (T233E)SPAK, WNK insensitive (T233A)SPAK, catalytically inactive (D212A)SPAK, wild-type OSR1, constitutively active (T185E)OSR1, WNK
insensitive (T185A)OSR1 and catalytically inactive (D164A)OSR1.
Glutamate-induced current was taken as measure of electrogenic glutamate
transport and was quantified utilizing dual electrode voltage clamp.
Furthermore, Ussing chamber was employed to determine glutamate
transport in the intestine from gene-targeted mice carrying WNK insensitive SPAK (spak(tg/tg)) and from corresponding wild-type mice (spak(+/+)).RESULTS:
EAAT3 activity was significantly decreased by wild-type SPAK and (T233E)SPAK, but not by (T233A)SPAK and (D212A)SPAK. SPAK decreased maximal transport rate without affecting significantly affinity of the carrier. Similarly, EAAT3 activity was significantly downregulated by wild-type OSR1 and (T185E)OSR1, but not by (T185A)OSR1 and (D164A)OSR1. Again OSR1 decreased maximal transport rate without affecting significantly affinity of the carrier. Intestinal electrogenic glutamate transport was significantly lower in spak(+/+) than in spak(tg/tg) mice.CONCLUSION:
Both, SPAK and OSR1 are negative regulators of EAAT3 activity.
EAAT3 activity was significantly decreased by wild-type SPAK and (T233E)SPAK, but not by (T233A)SPAK and (D212A)SPAK. SPAK decreased maximal transport rate without affecting significantly affinity of the carrier. Similarly, EAAT3 activity was significantly downregulated by wild-type OSR1 and (T185E)OSR1, but not by (T185A)OSR1 and (D164A)OSR1. Again OSR1 decreased maximal transport rate without affecting significantly affinity of the carrier. Intestinal electrogenic glutamate transport was significantly lower in spak(+/+) than in spak(tg/tg) mice.CONCLUSION:
Both, SPAK and OSR1 are negative regulators of EAAT3 activity.
16. 2015
Begum G, Yuan H, Kahle KT, Li L, Wang S, Shi Y, Shmukler BE, Yang SS, Lin SH, Alper SL, Sun D.
Stroke. 2015 Jul;46(7):1956-1965. doi: 10.1161/STROKEAHA.115.008939. Epub 2015 Jun 11.
- PMID:
- 26069258
17.2015
Tomaszewski
M, Eales J, Denniff M, Myers S, Chew GS, Nelson CP, Christofidou P,
Desai A, Büsst C, Wojnar L, Musialik K, Jozwiak J, Debiec R, Dominiczak
AF, Navis G, van Gilst WH, van der Harst P, Samani NJ, Harrap S,
Bogdanski P, Zukowska-Szczechowska E, Charchar FJ.
J Am Soc Nephrol. 2015 Dec;26(12):3151-60. doi: 10.1681/ASN.2014121211. Epub 2015 Apr 27.
- PMID:
- 25918036
18. 2014
Fezai M, Elvira B, Borras J, Ben-Attia M, Hoseinzadeh Z, Lang F.
Kidney Blood Press Res. 2014;39(6):546-54. doi: 10.1159/000368465. Epub 2014 Dec 8.
- PMID:
- 25531585
19.
Cai J, Hao CG, Luo DH, Du L, Zhang XY.
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2014 Jan;43(1):43-50. Chinese.
- PMID:
- 24616460
20. 2014
Zhu W, Begum G, Pointer K, Clark PA, Yang SS, Lin SH, Kahle KT, Kuo JS, Sun D.
Mol Cancer. 2014 Feb 20;13:31. doi: 10.1186/1476-4598-13-31.
- PMID:
- 24555568
