Antidepressants activate LPA1 lysophosphatidic acid receptor to induce growth factor receptor transactivation

Antidepressants (AD) are known to act on multiple molecular targets to modulate the activity of different neurotransmitter receptor systems. We previously reported that different classes of AD behave as partial agonists at opioid receptors in both homologous and heterologous cell systems. In the present study we show that the tricyclic AD amitriptyline, nortriptyline, imipramine and desipramine induce a concentration-dependent stimulation of extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in CHO/K1 cells endogenously expressing LPA1 lysophosphatidic acid (LPA) receptor. This response was completely antagonized by the LPA1 receptor antagonist Ki16425 with a potency similar to that displayed in blocking the response to LPA. The stimulation of ERK1/2 phosphorylation by AD and LPA was prevented by cell treatment with pertussis toxin, implying the involvement of G proteins of the Gi/Go family. Genistein, a wide spectrum tyrosine kinase inhibitor, and PP2, a selective Src-family tyrosine kinase inhibitor, abolished the AD response. Moreover, pharmacological blockade of insulin-like growth factor receptor by AG 1024 completely suppressed the amitriptyline-induced ERK1/2 phosphorylation. These data indicate that tricyclic AD can act as agonists at Gi/Go-coupled LPA1 receptor thereby promoting growth factor receptor transactivation and downstream signaling events.