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. Author manuscript; available in PMC: 2016 Aug 1.
Published in final edited form as: Trends Mol Med. 2015 Jul 1;21(8):513–523. doi: 10.1016/j.molmed.2015.05.008

Figure 1.

Figure 1

Cation-chloride cotransporters (CCCs) are key components of cell volume regulation. CCCs mediate transmembrane ion fluxes and can thereby increase or decrease cellular osmotic pressure. (A) Cell shrinkage (step 1) stimulates the WNK-STE20/SPS1-related proline/alanine-rich kinase (SPAK)/Oxidative stress response 1 (OSR1) kinase cascade (step 2), which triggers the phosphorylation of specific residues on both the N(K)CCs and the KCCs, causing their activation and inhibition, respectively (step 3). This net ionic influx of Na+, K+, and Cl−, coupled with obligatory water movement (step 4), restores cell volume in ‘regulatory volume increase’ (RVI). (B) Cell swelling (step 1) inhibits WNK-SPAK/OSR1 (step 2), and also stimulates protein phosphatases (such as PP1 and PP2A) that dephosphorylate N(K)CCs and the KCCs, causing their inhibition and activation, respectively (step 3). The resulting net ionic efflux of K+ and Cl−, coupled with obligatory water movement (step 4), restores cell volume in ‘regulatory volume decrease’ (RVD).