@article {Pergelmol.119.116269, author = {Eniko Pergel and Miklos Lengyel and Peter Enyedi and Gabor Czirjak}, title = {TRESK (K2P18.1) Background Potassium Channel is Activated by Novel-Type Protein Kinase C via Dephosphorylation}, elocation-id = {mol.119.116269}, year = {2019}, doi = {10.1124/mol.119.116269}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {TRESK (K2P18.1) background K+ channel is a major determinant of the excitability of primary sensory neurons. It has been reported that human TRESK is activated by the protein kinase C (PKC) activator PMA (phorbol 12-myristate 13-acetate) in Xenopus oocytes. In the present study, we investigated the mechanism of this PKC-dependent TRESK regulation. We show that TRESK is activated by the coexpression of the novel-type PKC isoforms eta and epsilon. The effect of PKC is not mediated by calcineurin phosphatase, which is known to evoke the calcium-dependent TRESK activation. The mutations of the calcineurin-binding sites in the channel (PQAAAS-AQAP) did not influence the PMA-induced increase of potassium current. In sharp contrast, the mutations of the target residue of calcineurin in TRESK, S264A and S264E, prevented the effect of PMA. The enforced phosphorylation of S264 by the coexpression of a microtubule-affinity regulating kinase construct (MARK2Δ) also abolished the PKC-dependent TRESK activation. These results suggest that in addition to calcineurin, PKC also regulates TRESK by changing the phosphorylation status of S264. The coexpression of PKC slowed down the recovery of the K+ current to the resting state after the calcineurin-dependent dephosphorylation of TRESK. Therefore, the likely mechanism of action is the PKC-dependent inhibition of the kinase responsible for the (re)phosphorylation of the channel at S264. The PKC-dependent dephosphorylation of TRESK protein was also detected by the Phos-tag SDS-PAGE method. In summary, the activation of novel-type PKC results in the slow (indirect) dephosphorylation of TRESK at the regulatory residue S264 in a calcineurin-independent manner.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2019/04/15/mol.119.116269}, eprint = {https://molpharm.aspetjournals.org/content/early/2019/04/15/mol.119.116269.full.pdf}, journal = {Molecular Pharmacology} }