The activation of STAT3 through functional coupling of G_i-coupled receptors with Gα₁₆ has been demonstrated previously. On the other hand, melatonin is a pleotropic indolehormone, modulating various biological responses mainly through its G_i-coupled melatonin membrane receptors. The aim of this research is to examine the STAT3 activation through functional coupling of melatonin receptors with Gα₁₆, to define the signaling intermediates involved, and any biological significance of this melatonin-induced STAT3 response. Immunoblotting with inhibitor treatment showed that the melatonin analogue 2-iodomelatonin can activate STAT3 through its stimulation of the melatonin receptors and Gα₁₆ stably expressed in HEK293 cells in a PTX-insensitive manner. In addition, multiple signaling intermedi...[ Read more ]

The activation of STAT3 through functional coupling of G_i-coupled receptors with Gα₁₆ has been demonstrated previously. On the other hand, melatonin is a pleotropic indolehormone, modulating various biological responses mainly through its G_i-coupled melatonin membrane receptors. The aim of this research is to examine the STAT3 activation through functional coupling of melatonin receptors with Gα₁₆, to define the signaling intermediates involved, and any biological significance of this melatonin-induced STAT3 response. Immunoblotting with inhibitor treatment showed that the melatonin analogue 2-iodomelatonin can activate STAT3 through its stimulation of the melatonin receptors and Gα₁₆ stably expressed in HEK293 cells in a PTX-insensitive manner. In addition, multiple signaling intermediates were involved in such response, including protein kinase C, protein kinase D (PKD), Src-family tyrosine kinases, JAK2, p38, MEK, as well as the production of autocrine factors. Apart from this, inhibitior treatment with PKC-specific inhibitor RO320432 at 1 μM and Gö6976 at 100 nM revelaed that PKCε may be the upstream kinase of PKD, and possible link between PKD and STAT3 was also demonstrated.