Two-Pore Domain Potassium Channel in Neurological Disorders

Activity of TREK-2-like Channels in the Pyramidal Neurons of Rat Medial Prefrontal Cortex Depends on Cytoplasmic Calcium

“…The preservation of mechanosensitivity in these experiments indicates that other factors than PI(4,5)P2 play a role in regulation by mechanical stimuli [31]. TREK channels are downregulated by the activation of G-coupled receptors activating phospholipase C, which hydrolyses PI (4,5)P2 to diacylglycerol (DAG) and inositol triphosphate (IP3), with the latter releasing Ca 2+ from internal stores. The depletion of PI(4,5)P2 caused by hydrolysis and the resulting loss of membrane interaction of the C-terminus inhibits TREK channels [30,32,33].…”

“…The role of PI (4,5)P2 in the gating of TREK channels is more complicated than just the stabilization of an active conformation by tethering the C-terminal domain to the plasma membrane, as the inhibition of TREK currents by PI(4,5)P2 was also observed. This inhibition occurred at higher concentrations of PI(4,5)P2 and was eliminated by pretreatment with poly-L-lysine [38].…”

“…Exogenous PI(4,5)P2 inhibited the spontaneous increase in TREK currents induced by ATP depletion. ATP inhibition of TREK channels can be mediated by phosphatidylinositol kinase, which increases the amount of PI (4,5)P2 in the plasma membrane, and the increase in PI (4,5)P2 has an inhibitory effect on TREK currents [21,[39][40][41]. This inhibitory effect of PI (4,5)P2 can be relieved by anionic phospholipids, such as phosphatidic acid, which is a TREK agonist.…”

“…ATP inhibition of TREK channels can be mediated by phosphatidylinositol kinase, which increases the amount of PI (4,5)P2 in the plasma membrane, and the increase in PI (4,5)P2 has an inhibitory effect on TREK currents [21,[39][40][41]. This inhibitory effect of PI (4,5)P2 can be relieved by anionic phospholipids, such as phosphatidic acid, which is a TREK agonist. An indirect stimulatory effect of PI(4,5)P2 on TREK currents may involve the production of phosphatidic acid by phospholipase D [42].…”

“…Medial prefrontal cortex lesions leading to cognitive impairment have been associated with various human brain disorders, such as depression, anxiety disorders, schizophrenia, autism spectrum disorders, Alzheimer’s disease, Parkinson’s disease, and addiction [ 3 ]. Some of these pathological processes may involve two-pore domain potassium channels (K2P), which are thought to play a significant role in neuronal excitability and in the resting membrane potential [ 4 ].…”