Inhibition of MAPK stimulates the Ca ²⁺ -dependent big-conductance K channels in cortical collecting duct

Abstract

The kidney plays a key role in maintaining potassium (K) homeostasis. K excretion is determined by the balance between K secretion and absorption in distal tubule segments such as the connecting tubule and cortical collecting duct. K secretion takes place by K entering principal cells (PC) from blood side through Na ؉ , K ؉ -ATPase and being secreted into the lumen via both ROMK-like small-conductance K (SK) channels and Ca 2؉ -activated big-conductance K (BK) channels. K reabsorption occurs by stimulation of apical K/H-ATPase and inhibition of K recycling across the apical membrane in intercalated cells (IC). The role of ROMK channels in K secretion is well documented. However, the importance of BK channels in mediating K secretion is incompletely understood. It has been shown that their activity increases with high tubule flow rate and augmented K intake. However, BK channels have a low open probability and are mainly located in IC, which lack appropriate transporters for effective K secretion. Here we demonstrate that inhibition of ERK and P38 MAPKs stimulates BK channels in both PC and IC in the cortical collecting duct and that changes in K intake modulate their activity. Under control conditions, BK channel activity in PC was low but increased significantly by inhibition of both ERK and P38. Blocking MAPKs also increased channel open probability of BK in IC and thereby it may affect K backflux and net K absorption Thus, modulation of ERK and P38 MAPK activity is involved in controlling net K secretion in the distal nephron.ERK MAPK ͉ K absorption ͉ K secretion ͉ P38 MAPK ͉ ROMK

Role of gp91phox-Containing NADPH Oxidase in Mediating the Effect of K Restriction on ROMK Channels and Renal K Excretion

“…34 In this regard, we previously demonstrated that low K intake stimulates the expression of protein kinase C. 35 Although this study is mainly focused on the role of superoxide anions in the regulation of ROMK channels, the finding that BK channels are inhibited by P38 and ERK MAPK, which are activated by superoxide anions, suggests that superoxide anions could also inhibit BK channels. 36 Several studies have convincingly demonstrated that BK channels are also involved in K secretion during high K intake and high tubule flow rate. [37][38][39] In addition, BK channels are present also in intercalated cells (IC) and could play a role in K recycling across the apical membrane of IC.…”

WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling

“…14,[16][17][18][19][20] In addition, MAPK was reported to inhibit BK channel activity in rat principal cells. 31 We have previously shown that WNK4 inhibits BK channel activity by enhancing its degradation through a lysosomal pathway. In this study, we found that overexpression of WNK1 increased BKa protein expressions while reducing ERK1/2 phosphorylation, whereas knockdown of WNK1 expression decreased BKa protein expression while increasing ERK1/2 phosphorylation.…”

“…30 Inhibition of mitogen-activated protein kinase (MAPK) stimulates BK activity in CCD cells. 31 Our previous study showed that WNK4 inhibits BK channel activity by enhancing its degradation via a lysosomal pathway. 7 WNK4 inhibits BK activity by activating extracellular signal-regulated kinase 1/2 (ERK1/2) and p-38 signaling pathways.…”

Implementing Patch Clamp and Live Fluorescence Microscopy to Monitor Functional Properties of Freshly Isolated PKD Epithelium

“…Similar patch-clamp and calcium measurements in nephron segments are widely used on non-cystic kidneys in many laboratories [41][42][43] . Depending ion channels type, different modifications of patch-clamp method can be used (whole cell, inside-out, outside-out); for instance, ENaC and ROMK (renal outer medullary potassium channel) activity can be assessed by whole-cell configuration 44,45 .…”