Although inhibition of presynaptic monoamine reuptake or metabo-lism is traditionally considered the main mechanism of action of an-tidepressants (AD), there is evidence that these drugs may also actthrough direct interaction with additional molecular targets, compris-ing distinct membrane receptors and ion channels. In the presentstudy, we show that, at therapeutically relevant concentrations, dif-ferent tricyclic AD, the tetracyclic AD mianserin and mirtazapineand the selective serotonin reuptake inhibitor fluoxetine inducegrowth factor receptor transactivation by triggering the activation ofLPA1lysophosphatidic acid (LPA) receptor. Thus, in CHO-K1 cells endogenously expressing LPA1receptors the stimulation of extracel-lular signal regulated kinases 1 and 2 (ERK1/2) phosphorylation byeither amitryptiline or mianserin was prevented by pertussis toxin,the Src tyrosine kinase inhibitor PP2, and the insulin-like growthfactor-1 receptor (IGF-1R) tyrosine kinase inhibitor AG1024. More-over, amitryptiline and mianserin induced IGF-1R and insulin recep-tor substrate 1 tyrosine phosphorylation. Cell treatment withKi16425, an antagonist of LPA1/LPA3receptors, or the selectiveLPA1receptor antagonist AM966, but not the selective LPA2recep-tor antagonist H2L5186303, blocked AD-induced ERK1/2 and IGF-1R phosphorylation. In HEK293 cells overexpressing the humanLPA1receptor, but not wild type cells, LPA and AD stimulatedERK1/2 phosphorylation and this response was blocked by Ki16425and AM966. AD failed to induce LPA3receptor activation in trans-fected CHO-K1 cells. As astrocytes express LPA1receptors and areconsidered to be a critical cellular target of AD, we investigatedwhether in rat C6 glioma cells activation of LPA1receptors wasinvolved in fibroblast growth factor receptor (FGF-R) transactivationby AD. We found that in these cells amitryptiline- and mianserin-induced phosphorylation of FGF-R, ERK1/2, Akt and the transcrip-tion factor CREB was significantly attenuated by either Ki16425 orAM966. The data indicate that different classes of AD triggergrowth factor receptor transactivation by enhancing LPA1receptoractivity. This novel pharmacological property may confer the abilityon AD to regulate proliferation, differentiation and survival of cellsexpressing LPA1receptors.
Involvement of LPA1 lysophosphatidic acid receptor activation in growth factor receptor transactivation by antidepressants
ONALI, PIER LUIGI;DEDONI, SIMONA;OLIANAS, MARIA CONCETTA
2014-01-01
Abstract
Although inhibition of presynaptic monoamine reuptake or metabo-lism is traditionally considered the main mechanism of action of an-tidepressants (AD), there is evidence that these drugs may also actthrough direct interaction with additional molecular targets, compris-ing distinct membrane receptors and ion channels. In the presentstudy, we show that, at therapeutically relevant concentrations, dif-ferent tricyclic AD, the tetracyclic AD mianserin and mirtazapineand the selective serotonin reuptake inhibitor fluoxetine inducegrowth factor receptor transactivation by triggering the activation ofLPA1lysophosphatidic acid (LPA) receptor. Thus, in CHO-K1 cells endogenously expressing LPA1receptors the stimulation of extracel-lular signal regulated kinases 1 and 2 (ERK1/2) phosphorylation byeither amitryptiline or mianserin was prevented by pertussis toxin,the Src tyrosine kinase inhibitor PP2, and the insulin-like growthfactor-1 receptor (IGF-1R) tyrosine kinase inhibitor AG1024. More-over, amitryptiline and mianserin induced IGF-1R and insulin recep-tor substrate 1 tyrosine phosphorylation. Cell treatment withKi16425, an antagonist of LPA1/LPA3receptors, or the selectiveLPA1receptor antagonist AM966, but not the selective LPA2recep-tor antagonist H2L5186303, blocked AD-induced ERK1/2 and IGF-1R phosphorylation. In HEK293 cells overexpressing the humanLPA1receptor, but not wild type cells, LPA and AD stimulatedERK1/2 phosphorylation and this response was blocked by Ki16425and AM966. AD failed to induce LPA3receptor activation in trans-fected CHO-K1 cells. As astrocytes express LPA1receptors and areconsidered to be a critical cellular target of AD, we investigatedwhether in rat C6 glioma cells activation of LPA1receptors wasinvolved in fibroblast growth factor receptor (FGF-R) transactivationby AD. We found that in these cells amitryptiline- and mianserin-induced phosphorylation of FGF-R, ERK1/2, Akt and the transcrip-tion factor CREB was significantly attenuated by either Ki16425 orAM966. The data indicate that different classes of AD triggergrowth factor receptor transactivation by enhancing LPA1receptoractivity. This novel pharmacological property may confer the abilityon AD to regulate proliferation, differentiation and survival of cellsexpressing LPA1receptors.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
