A new phospholipase-C–calcium signalling pathway mediated by cyclic AMP and a Rap GTPase

Abstract

Stimulation of phosphoinositide-hydrolysing phospholipase C (PLC) generating inositol-1,4,5-trisphosphate is a major calcium signalling pathway used by a wide variety of membrane receptors, activating distinct PLC-β or PLC-γ isoforms^1,2,3,4. Here we report a new PLC and calcium signalling pathway that is triggered by cyclic AMP (cAMP) and mediated by a small GTPase of the Rap family. Activation of the adenylyl cyclase-coupled β₂-adrenoceptor expressed in HEK-293 cells or the endogenous receptor for prostaglandin E₁ in N1E-115 neuroblastoma cells induced calcium mobilization and PLC stimulation, seemingly caused by cAMP formation, but was independent of protein kinase A (PKA). We provide evidence that these receptor responses are mediated by a Rap GTPase, specifically Rap2B, activated by a guanine-nucleotide-exchange factor (Epac) regulated by cAMP^5,6, and involve the recently identified PLC-ɛ isoform^7,8,9.