The K+ channel TASK1 modulates ß-adrenergic response in brown adipose tissue through the mineralocorticoid receptor pathway.

Brown adipose tissue (BAT) is essential for adaptive thermogenesis and dissipation of caloric excess through the activity of uncoupling protein (UCP)-1. BAT in humans is of great interest for the treatment of obesity and related diseases. In this study, the expression of Twik-related acid-sensitive K(+) channel (TASK)-1 [a pH-sensitive potassium channel encoded by the potassium channel, 2-pore domain, subfamily K, member 3 (Kcnk3) gene] correlated highly with Ucp1 expression in obese and cold-exposed mice. In addition, Task1-null mice, compared with their controls, became overweight, mainly because of an increase in white adipose tissue mass and BAT whitening. Task1(-/-)-mouse-derived brown adipocytes, compared with wild-type mouse-derived brown adipocytes, displayed an impaired ß3-adrenergic receptor response that was characterized by a decrease in oxygen consumption, Ucp1 expression, and lipolysis. This phenotype was thought to be caused by an exacerbation of mineralocorticoid receptor (MR) signaling, given that it was mimicked by corticoids and reversed by an MR inhibitor. We concluded that the K(+) channel TASK1 controls the thermogenic activity in brown adipocytes through modulation of ß-adrenergic receptor signaling.

Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.

Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin) and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out spadin as a putative antidepressant of new generation with a rapid onset of action. Spadin can be regarded as the first natural antidepressant peptide identified. It corresponds to a new concept to address the treatment of depression.

LRRC8/VRAC channels exhibit a noncanonical permeability to glutathione, which modulates epithelial-to-mesenchymal transition (EMT).

Volume-regulated anion channels (VRAC) are chloride channels activated in response to osmotic stress to regulate cellular volume and also participate in other cellular processes, including cell division and cell death. Recently, members of the LRRC8 family have been identified as the main contributors of VRAC conductance. LRRC8/VRAC is permeable to chloride ions but also exhibits significant permeability to various substrates that vary strongly in charge and size. In this study, we explored the intriguing ability of LRRC8/VRAC to transport glutathione (GSH), the major cellular reactive oxygen species (ROS) scavenger, and its involvement in epithelial-to-mesenchymal transition (EMT), a cellular process in which cellular oxidative status is a crucial step. First, in HEK293-WT cells, we showed that a hypotonic condition induced LRRC8/VRAC-dependent GSH conductance (PGSH/PCl of ~0.1) and a marked decrease in intracellular GSH content. GSH currents and GSH intracellular decrease were both inhibited by DCPIB, an inhibitor of LRRC8/VRAC, and were not observed in HEK293-LRRC8A KO cells. Then, we induced EMT by exposing renal proximal tubule epithelial cells to the pleiotropic growth factor TGFß1, and we measured the contribution of LRRC8/VRAC in this process by measuring (i) EMT marker expression (assessed both at the gene and protein levels), (ii) cell morphology and (iii) the increase in migration ability. Interestingly, pharmacologic targeting of LRRC8/VRAC (DCPIB) or RNA interference-mediated inhibition (LRRC8A siRNA) attenuated the TGFß1-induced EMT response by controlling GSH and ROS levels. Interestingly, TGFß1 exposure triggered DCPIB-sensitive chloride conductance. These results suggest that LRRC8/VRAC, due to its native permeability to GSH and thus its ability to modulate ROS levels, plays a critical role in EMT and might contribute to other physiological and pathophysiological processes associated with oxidative stress.