OSR1 and SPAK Sensitivity of Large-Conductance Ca2+ Activated K+ Channel

Abstract

Background/Aims: The oxidative stress-responsive kinase 1 (OSR1) and the serine/threonine kinases SPAK (SPS1-related proline/alanine-rich kinase) are under the control of WNK (with-no-K [Lys]) kinases. OSR1 and SPAK participate in diverse functions including cell volume regulation and neuronal excitability. Cell volume and neuronal excitation are further modified by the large conductance Ca²⁺-activated K⁺ channels (maxi K⁺ channel or BK channels). An influence of OSR1 and/or SPAK on BK channel activity has, however, never been shown. The present study thus explored whether OSR1 and/or SPAK modify the activity of BK channels. Methods: cRNA encoding the Ca²⁺ insensitive BK channel mutant BK^{M513I+Δ899-903} was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding wild-type OSR1 or wild-type SPAK, constitutively active ^T185EOSR1, catalytically inactive ^D164AOSR1, constitutively active ^T233ESPAK or catalytically inactive ^D212ASPAK. K⁺ channel activity was measured utilizing dual electrode voltage clamp. Results: BK channel activity in BK^{M513I+Δ899-903} expressing oocytes was significantly decreased by co-expression of OSR1 or SPAK. The effect of wild-type OSR1/SPAK was mimicked by ^T185EOSR1 and ^T233ESPAK, but not by ^D164AOSR1 or ^D212ASPAK. Conclusions: OSR1 and SPAK suppress BK channels, an effect possibly contributing to cell volume regulation and neuroexcitability.

Taurine depletion during fetal and postnatal development blunts firing responses of neocortical layer II/III pyramidal neurons

“…The mechanisms by which taurine depletion induces such modulation need further investigation. One possibility is the reduced signaling through the WNK kinase system under taurine-depleted conditions, because the WNK kinase and its downstream kinases of the SPS1-related proline/alanine-rich kinase (SPAK) and the oxidative stress-responsive kinase 1 (OSR1) have been reported to regulate several types of K + channels in other tissues ( Elvira et al, 2016 ; Taylor et al, 2018 ; Bi et al, 2020 ). In our recent microarray assay of signal transduction proteins in WT and TauT Homo KO brains ( Watanabe et al, 2022 ), the protein expression levels of the major WNK isoforms WNK1, WNK2 and WNK3, and the phosphorylation level of WNK1 at serine 382 were comparable between them ( Supplementary Table S1 ), although the phosphorylation levels of the other WNK isoforms were not investigated.…”

Stimulatory Role of SPAK Signaling in the Regulation of Large Conductance Ca2+-Activated Potassium (BK) Channel Protein Expression in Kidney

“…OSR1 is also expressed more than SPAK in cardiac tissues. It is generally accepted that SPAK can be phosphorylated by WNK ( O’Reilly et al, 2003 ; Vitari et al, 2005 , 2006 ; Delpire and Gagnon, 2006 ; Rafiqi et al, 2010 ; Glover et al, 2011 ) and then regulate a variety of ion transporters ( Fezai et al, 2014 , 2015b ; Warsi et al, 2014a , b ) and channels ( Falin et al, 2011 ; Elvira et al, 2014 , 2016 ; Warsi et al, 2014c ; Ahmed et al, 2015 ; Fezai et al, 2015a ), such as sodium chloride cotransporter (NCC) and sodium potassium chloride cotransporter (NKCC), potassium chloride cotransporter (KCl), and Na + /H + exchanger (NHE). BK acts as a K + channel that plays a major regulatory role in K secretion in the kidney, which is responsible for flow-dependent K + secretion, and it is also involved in the regulation of blood pressure.…”

“…Since BK is a calcium-and voltage-activated K channel, the Cainsensitive BK mutant might exhibit a different channel activity in response to SPAK signaling. In the present study, WT BK constructs have been used for all the experiments, which might explain why findings from the present study are different from the previous report (Elvira et al, 2016). Whether the calcium sensor domain in the BK channel confers different responses of BK to SPAK kinase remains to be explored.…”