Prostaglandin E2 both stimulates and inhibits adenyl cyclase on platelets: comparison of effects on cloned EP4 and EP3 prostaglandin receptor subtypes.
The effects of prostaglandin E2 (PGE2) on platelet cyclic AMP formation were examined and compared with effects on cloned prostaglandin receptors. PGE2 gave a weak stimulation of adenyl cyclase in platelets compared with the PGI2 analog Iloprost. In the presence of the adenyl cyclase stimulator forskolin, the response to PGE2 was amplified in a synergistic manner. By contrast, in the presence of Iloprost, PGE2 inhibited cyclic AMP formation. We postulate that the weak platelet response to PGE2 is due to co-localization of a PGE2 receptor that couples to stimulation of adenyl cyclase with the EP3 prostaglandin receptor that binds PGE2 tightly and inhibits adenyl cyclase. In support of this postulate, we compared the responses obtained with platelets with those of cloned EP4 (stimulatory) and EP3 (inhibitory) prostaglandin receptor subtypes and show similar dose-response curves for stimulation and inhibition of cyclic AMP formation between platelets and cloned receptors.
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
G F
GF
Mao
J G
JG
Jin
M
M
Bastepe
S
S
Ortiz-Vega
B
B
Ashby
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000187:drug effects*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
D000067956:Adenylyl Cyclase Inhibitors; C545647:PTGER3 protein, human; C545650:PTGER4 protein, human; D010975:Platelet Aggregation Inhibitors; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D016285:Iloprost; D015232:Dinoprostone