Abstract
Pharmacological analysis of in vivo cAMP phosphodiesterase in Xenopus oocytes using the nonselective enzyme inhibitors 3-isobutyl-1-methylxanthine (IBMX), theophylline, and papaverine, demonstrated inhibition of insulin- and insulin-like growth factor-1-induced maturation at concentrations that were 17-60-fold lower than those required to inhibit progesterone-induced germinal vesicle breakdown. The abilities of the phosphodiesterase inhibitors to block the maturation response showed the same rank order of potencies for each hormone: papaverine greater than IBMX greater than theophylline. Insulin-induced oocyte maturation that was accelerated by 0.01 microM progesterone was also inhibited by low micromolar concentrations of IBMX, demonstrating that the accelerated time course was due to a synergistic potentiation of insulin action by progesterone. Both insulin-induced maturation and insulin-stimulated phosphodiesterase activity displayed similar sensitivities to inhibition by IBMX, suggesting that hormone-stimulated phosphodiesterase activity is required for the peptide hormone action. Furthermore, microinjection of the transforming ras gene product [Val12,Thr59]Ha induced oocyte maturation and stimulated oocyte phosphodiesterase activity by approximately 50%, and both of these actions were inhibited by IBMX. These results suggest that oocyte maturation induced by insulin, insulin-like growth factor 1, and transforming ras protein involves stimulation of a similar phosphodiesterase.
Highlights
Pharmacological analysis of in vivocAMP phospho- adenylate cyclase has been correlated with binding of steroid diesterase in Xenopus oocytes using the nonselective to a plasma membrane receptor [4] and slowing of guanine enzymeinhibitors3-isobutyl-1-methylxanthine nucleotide exchange [5].,incontrast to other (IBMX), theophylline, and papaverine, demonstrated cell systems in which the actions of inhibitory hormones on inhibition of insulin- and insulin-like growth factor-linduced maturation at concentrations that were 17
These in uitro data gave no indication of hormone sensitivity, and it has been suggested that calmodulin activation of oocyte phosphodiesterase activity is inhibited in living oocytes [25]
Even though it haslong been known that theophylline and related xanthines inhibit progesterone-induced oocyte maturation [26,27,28], the present study is the first to compare the abilities of IBMX, theophylline, and papaverine to inhibit oocyte maturation stimulated by progesterone, insulin, and IGF-1
Summary
Pharmacological analysis of in vivocAMP phospho- adenylate cyclase has been correlated with binding of steroid diesterase in Xenopus oocytes using the nonselective to a plasma membrane receptor [4] and slowing of guanine enzymeinhibitors3-isobutyl-1-methylxanthine nucleotide exchange [5].,incontrast to other (IBMX), theophylline, and papaverine, demonstrated cell systems in which the actions of inhibitory hormones on inhibition of insulin- and insulin-like growth factor-linduced maturation at concentrations that were 17-. When theophylline and IBMX were used to characterize hormone-induced oocyte maturation, the actions of insulin and IGF-1could be clearly distinguished from that of progesterone onthe basis of the observed sensitivities to inhibition.
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