GF-109203X

Leukotrienes (LTs) are potent bioactive lipids derived from the 5‐lipoxygenase (5‐LOX)‐mediated metabolism of arachidonic acid (AA). Growing evidence suggests that leukotrienes contribute to the pathophysiology of several inflammatory disorders of the central nervous system. However, the molecular mechanisms by which cysteinyl leukotrienes (CysLTs) facilitate excitatory activity remain poorly understood. Sodium/potassium‐ATPase (Na + /K + ‐ATPase) is a plasma membrane protein essential for maintaining ionic gradients and regulating membrane excitability, and its reduced activity has been implicated in increased excitability within the central nervous system. In the present study, we demonstrate that LTD 4 decreases Na + /K + ‐ATPase activity (α 1 and α 2/3 subunits) in hippocampal slices from adult male Swiss mice. Furthermore, the intracerebroventricular (i.c.v.) administration of LTD 4 reduced Na + /K + ‐ATPase activity ex vivo, reinforcing the pathophysiological relevance of our in vitro findings. The LTD 4 ‐induced decrease in Na + /K + ‐ATPase activity was prevented by both the CysLT 1 receptor (CysLT 1 R) inverse agonist montelukast and an anti‐CysLT 1 R antibody, as well as by the PKC inhibitor GF109203X. Moreover, LTD 4 increased PKC phosphorylation and enhanced Ser‐16 phosphorylation of Na + /K + ‐ATPase. These effects were also prevented by PKC inhibition. In summary, our findings demonstrate that CysLT 1 R activation inhibits hippocampal Na + /K + ‐ATPase activity in mice through a PKC‐dependent mechanism, providing a potential molecular basis for LTD 4 involvement in the pathophysiology of various neurological disorders. image

Long-term depression (LTD), a form of synaptic plasticity, is impaired in the nucleus accumbens (NAc) in depression. While TRPV4 activation regulates synaptic transmission in the hippocampus, its effects in the NAc remain unclear. Here, we examined the effects of TRPV4 activation on LTD induction in the NAc and depressive-like behavior. Mice that were administered the TRPV4 agonist GSK1016790A into the NAc (GSK-mice) showed depressive-like behavior and impaired LTD induction in NAc slices. Additionally, the mRNA and protein levels of dopamine D2 receptor (D2R) and A-type gamma-aminobutyric acid receptor (GABA_AR) were markedly decreased in the NAc of GSK-mice. Meanwhile, administering a D2R (quinpirole) or GABA_AR (muscimol) agonist reversed LTD impairment in the NAc. The protein levels of phosphorylated protein kinase C (p-PKC) increased markedly and that of phosphorylated protein kinase B (p-Akt) decreased in the NAc of GSK mice. Administration of a PKC antagonist (GF109203X) or phosphatidylinositol 3-kinase (PI3K) agonist (740 Y-P) significantly increased GABA_AR protein levels and restored LTD induction in the NAc of GSK-mice. Administration of quinpirole increased p-Akt and GABA_AR protein levels in the NAc of GSK-mice. Finally, administration of quinpirole, muscimol, GF109203X or 740 Y-P improved the depressive-like behavior in GSK-mice. This study suggests that activation of TRPV4 impairs LTD induction in the NAc and induces depressive-like behavior, which is likely mediated by down-regulating D2R to inhibit PI3K-Akt pathway, and activating PKC to decrease the expression of GABA_AR.