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

Nat Cell Biol. 2001 Nov;3(11):1020-4. doi: 10.1038/ncb1101-1020.


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-beta or PLC-gamma isoforms. 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 beta2-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, and involve the recently identified PLC-epsilon isoform.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Alprostadil / metabolism
  • Calcium Signaling*
  • Cell Line
  • Cyclic AMP / metabolism*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Phosphoinositide Phospholipase C
  • Receptors, Adrenergic, beta / genetics
  • Receptors, Adrenergic, beta / metabolism
  • Tumor Cells, Cultured
  • Type C Phospholipases / genetics
  • Type C Phospholipases / metabolism*
  • rap GTP-Binding Proteins / metabolism*


  • Guanine Nucleotide Exchange Factors
  • RAPGEF3 protein, human
  • Receptors, Adrenergic, beta
  • Cyclic AMP
  • Type C Phospholipases
  • Phosphoinositide Phospholipase C
  • phospholipase C epsilon
  • RAP2B protein, human
  • GTP-Binding Protein alpha Subunits, Gs
  • rap GTP-Binding Proteins
  • Adenylyl Cyclases
  • Alprostadil