Abstract
Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global disease are scanty. Cation-chloride cotransporters (CCCs) are expressed in several tissues (including neurons) and extensively contribute to the maintenance of numerous physiological functions including chloride homeostasis. Previous studies have implicated two CCCs, the Na+-K+-Cl− and K+-Cl− cotransporters (NKCCs and KCCs) in stroke episodes along with their upstream regulators, the with-no-lysine kinase (WNKs) family and STE20/SPS1-related proline/alanine rich kinase (SPAK) or oxidative stress response kinase (OSR1) via a signaling pathway. As the WNK-SPAK/OSR1 pathway reciprocally regulates NKCC and KCC, a growing body of evidence implicates over-activation and altered expression of NKCC1 in stroke pathology whilst stimulation of KCC3 during and even after a stroke event is neuroprotective. Both inhibition of NKCC1 and activation of KCC3 exert neuroprotection through reduction in intracellular chloride levels and thus could be a novel therapeutic strategy. Hence, this review summarizes the current understanding of functional regulations of the CCCs implicated in stroke with particular focus on NKCC1, KCC3, and WNK-SPAK/OSR1 signaling and discusses the current and potential pharmacological treatments for stroke.
Highlights
This review summarizes the current understanding of functional regulations of the cation-chloride cotransporters (CCCs) implicated in stroke with particular focus on NKCC1, KCC3, and with-no-lysine kinase (WNKs)-SPS1-related proline/alanine rich kinase (SPAK)/OSR1 signaling and discusses the current and potential pharmacological treatments for stroke
A group of three Na+ -dependent inward cotransporters comprises of one Na+ -Cl− cotransporter (NCC)—its sole isoform is found in the kidney and encoded by SLC12A3 [9] and two Na+ -K+ -Cl− cotransporters isoforms (NKCC1 and 2)—NKCC1 is ubiquitous whilst NKCC2 is expressed in the kidney and are encoded by SLC12A2 and SLC12A1, respectively [2]
The established role of WNK-SPAK/OSR1 signaling pathway in stimulating NKCC1 and inhibiting KCC3, which contribute to the pathogenesis of stroke, are the reasons for our recent pharmacological studies [70,71]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The family of cation-chloride cotransporters (CCCs) comprises the Na+ -K+ -Cl− , Na+ and K+ -Cl− cotransporters (NKCCs, NCC, and KCCs) Identification of these CCCs in several tissues such as red blood cells, epithelia, and neurons have alluded to their extensive contributions to ion and water homeostasis, both at a cellular and trans-epithelial level [1,2,3]. All proteins in the CCC family have common functional characteristics These include (1) the coupled transport of one cation (Na+ and/or K+ ) per individually transported anion, the appellation of electroneutral cotransporters, (2) chloride is always the transported anion, (3) all cotransporters are modulated by variations in cell volume, (4) changes in the intracellular chloride concentration ([Cl− ]i ) influence the modulation of their expression, and (5) the regulation of CCCs activity is achieved through phosphorylation and dephosphorylation processes [19]. Current pharmacological treatments for stroke with respect to potent inhibitors of WNK-SPAK/OSR1 pathway and NKCC1 cotransporter, and activators of KCC3 transporter will be discussed in this review
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