CysLT1 Receptor Activation Decreases Na+/K+-ATPase Activity via PKC-Mediated Mechanisms in Hippocampal Slices

Abstract

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 LTD₄ decreases Na⁺/K⁺-ATPase activity (α₁ and α_2/3 subunits) in hippocampal slices from adult male Swiss mice. Furthermore, the intracerebroventricular (i.c.v.) administration of LTD₄ reduced Na⁺/K⁺-ATPase activity ex vivo, reinforcing the pathophysiological relevance of our in vitro findings. The LTD₄-induced decrease in Na⁺/K⁺-ATPase activity was prevented by both the CysLT₁ receptor (CysLT₁R) inverse agonist montelukast and an anti-CysLT₁R antibody, as well as by the PKC inhibitor GF109203X. Moreover, LTD₄ 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 CysLT₁R activation inhibits hippocampal Na⁺/K⁺-ATPase activity in mice through a PKC-dependent mechanism, providing a potential molecular basis for LTD₄ involvement in the pathophysiology of various neurological disorders.