TWIK-related spinal cord K+ channel (TRESK) is the gene product of KCNK18, the last discovered leak potassium K2P channel gene. Under resting conditions, TRESK is constitutively phosphorylated at two regulatory regions. Protein kinase A (PKA) and microtubule affinity-regulating (MARK) kinases can be applied in experiments to phosphorylate these sites of TRESK expressed in Xenopus oocytes, respectively. Upon generation of a calcium signal, TRESK is dephosphorylated and thereby activated by calcineurin. In this process, the binding of calcineurin to the channel by non-catalytic interacting sites is essential. The phosphorylation/dephosphorylation regulatory process is modified by 14-3-3 proteins.