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. Author manuscript; available in PMC: 2020 Jan 10.
Published in final edited form as: Neurosci Lett. 2018 Jan 9;689:33–44. doi: 10.1016/j.neulet.2018.01.012

Fig. 3. Cl− as an intracellular signaling ion.

Fig. 3

Recent findings identified the With No lysine [K] (WNK) protein kinases as intracellular [Cl−] sensors. Binding of Cl−, which occurs in the N-terminal activation loop of WNK1-4, inhibits autophosphorylation and activity of these enzymes. Reductions in [Cl−]i promote WNK1-4 autophosphorylation and activation. Active WNKs phosphorylate and stimulate two closely related protein kinases SPAK/OSR1, which in turn phosphorylate NKKC1 and KCC1-4. The functional effects of phosphorylation on cation-Cl− cotransporters are opposite: activation of NKCC1 and inhibition of KCC1-4. When WNKs are inactive, NKCC1 and KCC1-4 are dephosphorylated by the serine/threonine protein phosphatases PP1 and PP2A. See text for additional details.