Exploring the Role of the SLC12A Cation-Coupled Chloride Cotransporters in the Cardiovascular System

Figures

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  Figure 1. Phospho-regulation of CCCs via the WNK-SPAK/OSR1-CCC pathway. In response to hypertonic or low-chloride stimuli (left blue), WNK kinases become activated through autophosphorylation [75], subsequently phosphorylating and activating their main downstream targets, the SPAK/OSR1 kinases [2,68,77]. SPAK/OSR1 phosphorylates the CCCs, thereby activating the transport of Na, Cl, and K ions into the cell via the cotransporters NCC-NKCC1/2. In turn, the K cotransporters (KCCs) are inhibited [70,73,79,81,82]. In response to hypotonic or Cl-increasing stimuli (right red), the WNK-SPAK/OSR1 kinases become dephosphorylated and inactive, marking the onset of PP1 activity [1,68,69], which dephosphorylates the CCCs, promotes extrusion of K and Cl ions via activated KCCs, and inhibits NCC-NKCC1/2 under these conditions.

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  Figure 2. Cardiac protein expression of human SLC12A/CCCs. With the exception of NKCC2, NCC, and KCC2, all other cotransporters are expressed within the myocardial chambers: left atrium, left ventricle, and right atrium. None of the CCCs are expressed in the right ventricle. ✔, evidence of expression; NE, no evidence of expression. (Red—NKCC1; green—KCC1; blue—KCC3; yellow—KCC4.) Modified from Cardiac Proteome (https://cardiacproteomics.com).

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  Figure 3. Expression and function of KCCs in the heart. KCCs expressed in the myocardium perform functions such as epithelial transport of electrolytes, regulation of intracellular chloride balance, and regulation of cell volume, which are important for maintaining cardiac excitability and myogenic tone. Dysfunction of KCC isoforms contributes to the development of various pathologies, such as arrhythmias, hypertrophy, hypertension, and heart failure [6,9,12,14,17,96,117,118,119,120,121].

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  Figure 4. The role of WNK kinases in the cardiovascular system and in hypochloremia. In the kidney, WNK kinase activity (primarily WNK1 and WNK4) modulates the activation of Na cotransporters (NCC, NKCC2—blue bars) by sensing a decrease in intracellular Cl [2,68,77]. In the kidney, mutations in WNK are associated with the development of type II pseudo-hypoaldosteronism (PHAII), also known as Gordon syndrome, which causes elevated blood pressure [151,152]. In the cardiovascular system, WNK1 and WNK3 regulate the activity of NKCC1 and the KCCs, primarily by regulating intracellular Cl levels through a balance between the influx activity of NKCC1 and the efflux activity of the KCCs [153,154,155,156,157,161], both of which are important for maintaining vascular tone and vasoconstriction. In the hypochloremia cycle (red arrows and tables), the drop in surrounding Cl triggers activation of WNK kinases in the kidney, which in turn activate the NCC cotransporter and increase Na uptake. The increase in NCC activity is associated with a rise in blood pressure [79,86,88].