THE MEL(1A) MELATONIN RECEPTOR IS COUPLED TO PARALLEL SIGNAL-TRANSDUCTION PATHWAYS

The recent cloning of a family of high affinity melatonin receptors ha s provided us with a unique opportunity to define the signal transduct ion pathways used by these receptors. We have studied signaling throug h the human Mel(1a) receptor subtype by stable expression of receptor complementary DNA in NIH 3T3 cells. Our data indicate that the human M el(1a) receptor is coupled to inhibition of forskolin-stimulated cAMP accumulation by a pertussis toxin-sensitive G protein. Although melato nin alone is without effect on phosphoinositide hydrolysis, it potenti ates the effects of PGF(2 alpha) stimulation on phospholipase C activa tion. Melatonin potentiates arachidonate release stimulated by PGF(2 a lpha) and by ionomycin. The effects of melatonin on arachidonate relea se are sensitive to inhibition of protein kinase C. They are independe nt of the effects of melatonin on cAMP and do not appear to involve ac tivation of mitogen-activated protein kinase. The effects of melatonin on both phosphoinositide hydrolysis and arachidonate release are sens itive to pertussis toxin treatment. Thus, we show that the melatonin s ignal is transduced by parallel pathways involving inhibition of adeny lyl cyclase and potentiation of phospholipase activation.