L-WNK1 is required for BK channel activation in intercalated cells

Abstract

BK channels expressed in intercalated cells (ICs) in the aldosterone-sensitive distal nephron (ASDN) mediate flow-induced K+ secretion. In the ASDN of mice and rabbits, IC BK channel expression and activity increase with a high K+ diet. In cell culture, the long isoform of the kinase WNK1 (L-WNK1) increases BK channel expression and activity. Apical L-WNK1 expression is selectively enhanced in ICs in the ASDN of rabbits on a high K+ diet, suggesting that L-WNK1 contributes to BK channel regulation by dietary K+. We examined the role of IC L-WNK1 expression in enhancing BK channel activity in response to a high K+ diet. Mice with an IC-selective deletion of L-WNK1 (IC-L-WNK1-KO) and littermate control mice were placed on a high K+ (5% K+ as KCl) diet for at least 10 days. IC-L-WNK1-KO mice exhibited higher blood K+ concentrations ([K+]) than controls. BK channel-dependent whole-cell currents in ICs from cortical collecting ducts of high K+ fed IC-L-WNK1-KO mice were reduced compared to controls. Six-hour urinary K+ excretion in response a saline load was similar in IC-L-WNK1-KO mice and controls. The observations that IC-L-WNK1-KO mice have higher blood [K+] and reduced IC BK channel currents are consistent with impaired urinary K+ secretion, and suggest that IC L-WNK1 has a role in the renal adaptation to a high K+ diet.

Chloride oscillation in pacemaker neurons regulates circadian rhythms through a chloride-sensing WNK kinase signaling cascade

“…NKCC1, KCCs and WNK3 are expressed in the rat SCN (Belenky et al, 2010). The repertoire of ion channels regulating pacemaker neuron excitability is complex and incompletely understood, but large-conductance Ca 2+ -activated potassium channels (also known as BK or maxi-K) have been implicated, and are regulated by mammalian WNKs (Harvey et al, 2020;Liu et al, 2014;Ray et al, 2021;Wang et al, 2013;Webb et al, 2016;Yue et al, 2013;Zhuang et al, 2011). Whether the oscillating intracellular chloride observed in SCN neurons regulates these or other ion channels underlying SCN neuron electrical properties will be of interest.…”

WNK1 in the kidney

“…2). In vivo , decreased BK-mediated currents were observed in mice with selective deletion of L-WNK1 in intercalated cells [51 ▪ ]. After 10 days in HKD, knockout mice had higher plasma K + levels than their wild-type littermates, supporting a role for L-WNK1 mediated regulation of BK for the renal adaptation to HKD.…”