Mediation of PACAP-like neuropeptide transmission by coactivation of Ras/Raf and cAMP signal transduction pathways in Drosophila

MUCH work on the signal transduction mechanisms underlying neurotransmission has been directed towards studying the roles of the cyclic AMP and phosphoinositide pathways^1-3. Upon ligand binding, the transmitter receptors interact with heterotrimeric G proteins, allowing G_α and G_βγ subunits to disengage^2,3. The free G_α then modulates the activity of adenylyl cyclase and phospholipase C^1-3. It has been suggested that the G_βγ complex which is activated through muscarinic or neuropeptide receptors can stimulate mitogen-activated protein kinase (MAPK) via activation of the small guanine-nucleotide-binding protein Ras^4,5. Sequential activation of the intermediates in the Ras/Raf serine-threonine protein kinase/MAPK kinase/MAPK/transcription factor pathway has emerged as a central mechanism for controlling cell proliferation and differentiation in yeast, worms, fruitflies and mammals^6-11. Here we show, by analysis of Drosophila mutants, that synaptic current and modulation of K⁺ current, triggered by a pituitary adenylyl cyclase-activating polypeptide-like neuropeptide¹², are mediated by coactivation of the Ras/Raf and Ruta-aga-adenylyl cyclase pathways. Thus the Ras/Raf pathway also appears to be essential for G-protein-coupled neurotransmission.