A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase.
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.
Schmidt
M
M
Institut für Pharmakologie, Universitätsklinikum Essen, 45122 Essen, Germany. martina.schmidt@uni-essen.de
Evellin
S
S
Weernink
P A
PA
von Dorp
F
F
Rehmann
H
H
Lomasney
J W
JW
Jakobs
K H
KH
D000262:Adenylyl Cyclases / Q000378:metabolism; D000527:Alprostadil / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D054801:Phosphoinositide Phospholipase C; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*; D020668:rap GTP-Binding Proteins / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; C065562:RAP2B protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D020668:rap GTP-Binding Proteins; D000262:Adenylyl Cyclases; D000527:Alprostadil