|Titolo:||Tricyclic and tetracyclic antidepressants activate LPA1 lysophosphatidic acid receptor signaling in glial cells. 44th Meeting of the Society for Neuroscience. 15-19 November 2014 Washington, U.S.A.|
|Data di pubblicazione:||2014|
|Abstract:||Although inhibition of presynaptic monoamine reuptake or metabolism is generally considered the main mechanism of action of antidepressants (AD), there is a large body of evidence indicating that the pharmacological actions of these drugs can also derive from their direct interaction with additional molecular targets. We have previously reported that different classes of AD can activate LPA1 lysophosphatidic acid (LPA) receptor in Chinese hamster ovary cells to induce growth factor receptor transactivation. In the present study we extended this observation by examining the ability of different AD to induce LPA1 signaling in glial cells, which are considered a relevant cellular target of AD therapeutic action. We found that in C6 glioma cells the tricyclic AD amitriptyline, desipramine, imipramine and nortriptyline, the tetracyclic AD mianserin and mirtazapine increased the phosphorylation state of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in a pertussis toxin (PTX)-sensitive manner. The LPA1/3 antagonist Ki16425 and the selective LPA1 antagonist AM966 reduced the stimulatory effect on ERK1/2 phosphorylation elicited by either amitriptyline, mianserin or LPA. The LPA receptor antagonists also counteracted the increased phosphorylation of the transcription factor CREB and the prosurvival protein kinase Akt induced by either amitriptyline or mianserin. Similar results were obtained in rat cortical astrocytes, where amitriptyline and mianserin activated ERK1/2 in a manner sensitive to PTX, Ki16425 and AM966. Moreover, treatment of C6 glioma cells with LPA1 siRNA inhibited ERK1/2 phosphorylation by amitriptyline and mianserin. The data provide evidence that in glial cells tricyclic and tetracyclic AD activate LPA1 receptor coupled to signaling pathways regulating cell survival and differentiation.|
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