A potential mechanism for copper amplification of prostaglandin E2 action: attenuation of prostaglandin E2-induced efflux of cyclic AMP from median eminence explants.
It is known that prostaglandin E2 (PGE2) stimulation of LHRH release from the median eminence-arcuate nucleus (MEA) is mediated by the cAMP pathway, and a short pretreatment with copper markedly amplifies this release process. Because stimulation of cAMP accumulation is accompanied by cAMP efflux in many tissues, we considered the possibility that attenuation of cAMP efflux is one mechanism by which copper can enhance PGE2 action. When rat MEA explants were incubated in vitro, PGE2 induced a rapid (less than 2.5 min) and sustained (15 min) increase in cAMP efflux, the degree of which was a function of [PGE2]: by 5 min exposure to 10 microM PGEs2, efflux was 8-fold greater than the control (no PGE2) and it accounted for 12.4% of the total (tissue + medium) cAMP. Unlike the dramatic increase in cAMP efflux, PGE2 induced a moderate increase in cAMP content (49%) and in the incorporation of [3H] adenine into [3H] cAMP (78%); this increase was transient: it was evident after a 2.5 but not after a 5 min period of PGE2 exposure. Copper pretreatment did not alter this PGE2-induced increase in tissue cAMP content. In contrast, copper markedly inhibited (by 49%-66%) PGE2-induced cAMP efflux and this inhibition was noted regardless of the length of PGE2 exposure and PGE2 concentration. There was no evidence for hydrolysis of [3H]3',5'-cAMP included in the medium during the incubation with PGE2 with and without copper pretreatment. In summary, copper attenuated PGE2-induced cAMP efflux from MEA explants and this attenuation is not a consequence of a reduction in the availability of intracellular cAMP nor of hydrolysis of cAMP extracellularly.
Magni
P
P
Department of Obstetrics and Gynecology, University of Texas, Southwestern Medical Center, Dallas 75235-9032.
Barnea
A
A
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D003300:Copper / Q000008:administration & dosage*; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000008:administration & dosage*; D004357:Drug Synergism; D066298:In Vitro Techniques; D008297:Male; D008473:Median Eminence / Q000187:drug effects / Q000378:metabolism; D051381:Rats
D003300:Copper; D000242:Cyclic AMP; D015232:Dinoprostone