Influence of relaxin and insulin on the activity of adenylate cyclase in the myometrium of pregnant women with type 1 diabetes mellitus

Abstract

The study of the influence of relaxin and insulin on the activity of adenylate clase (AC) in the myometrium of pregnant women showed that human relaxin 2 (10-9-10-8 M) causes a stronger stimulating effect on the enzyme activity than insulin. The activating effect of relaxin and insulin was potentiated by a non-hydrolyzable GTP analogue, guanylylimidodiphosphate (GIDP), in the myometrium of pregnant women, which indicates the participation of the stimulating GTP-binding protein (Gs-protein) in the realization of the effect of peptides. In the myometrium of pregnant women with type 1 diabetes mellitus under the action of relaxin, insulin and isoproterenol, a decrease in the sensitivity of AC activity to these hormones was found in comparison with these indicators in the myometrium of pregnant women. With the combined effect of peptides and GIDP in the myometrium of pregnant women with type 1 diabetes mellitus, a weakening of the potentiation of the GIDP effect of hormones on AC activity was observed, which may indicate a decrease in the coupling between receptors, Gs protein, and AC. The studies carried out allow us to conclude that in pregnant women with type 1 diabetes mellitus, the decrease in AC stimulation under the influence of these hormones is associated with a weakening of the Gs-protein function.

Keywords

relaxin / insulin / adenylate cyclase / diabetes / myometrium

References

[1] Pertseva M.N., Plesneva S.A., Shpakov А.О., Rusakov Yu.I., Kuznetsova L.A. Involvement of adenylyl cyclase signalling system in the action of insulin and mollusc insulin-like peptide. Comp. Biochem. Physiol. — 1995. - Vol.1l2.-P. 689-695.

[2] Pertseva M.N., Plesneva S.A., Kuznetsova L.A., Shpakov A.O., Derkach K.V. On the tyrosine kinase mechanism of the novel effect of insulin and insulin-like growth factor-l: Stimulation of adenylyl cyclase system in muscle tissues. Biochem. Pharmacol. - 1996. - Vol. 52. - P. 1867-1874.

[3] Pertseva M.N., Shpakov A.O., Plesneva S.A., Kuznetsova L.A. A novel view on the mechanism of action of insulin and other insulin superfamily peptides: involvement of adenylyl cyclase signaling system. Comp. Biochem. Physiol. - 2003. - Vol. 134. - P. 11-34.

[4] Kuznetsova L., Plesneva S., Derjabina N., Omeljaniuk E., Pertseva M.N. On the mechanism of relaxin action: the involvement of adenylyl cyclase signalling system. Regul. Peptides. - 1999. - Vol. 80. - P. 33-39.

[5] Плеснева C.A., Кузнецова Л.А. Омелъянюк Е.В., Шпаков А.О., Перцева М.Н. Аденилатциклазный сигнальный механизм действия релаксина //Ж. эвол. биох. физиол. -2000. -Т. 36. - С. 562-568.

[6] Bryant-Greenwood G.D. and Schwabe C. Human relaxins: chemistry and biology. End. Rev. - 1994. - Vol. 15. - P. 5-26.

[7] Bullesbach E.E., Yang S., Schwabe C. The receptor — binding site of human relaxin 2. A dual prong — binding mechanism. J. Biol. Chem. - 1992. - Vol. 267. - P. 22957-22960.

[8] Кузнецова Л.А. Регуляторные свойства изоформ аденилатциклаз//Ж. эвол. биох. физиол. - 2002. - Т. 38. - С. 289-304.

[9] Mcllwrath A., Downing S.J., Hollingsworth М. Relaxin and сАМР in rat uterus in vivo, Biochem. Soc. Transact. - 1991. - Vol. 19. - P. 356S.

[10] Hughes S.J., Hollingsworth M., Elliot K.R. The role of a сАМР-dependent pathway in the uterine relaxant action of relaxin in rats //J. Reprod. Fertil. - 1997. - Vol. 109. — P. 289-296.

[11] Cronin M. J., Malaska T., Bakhit C. Human relaxin increases cyclic AMP levels in cultured anterior pituitary cells//Biochem. Biophys. Res. Commun. - 1987. - Vol. 148. -P. 1246-1251.

[12] Bigazzi M., Brandi M.L., Bani G., Bani Sacchi T. Relaxin influences the growth of MCF-7 brast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration//Cancer. - 1992. - Vol. 70. - P. 639-643.

[13] Hsu SY, Nakabayashi K., Nishi S., Kumagai J., Kudo M., Sherwood O.D., Hsueh A.J. Activation of orphan receptors by the hormone relaxin//Science. — 2002. — Vol. 295. - P. 671-4.

[14] Salomon Y., Londons C., Rodbell M. A highly sensitive adenylate cyclase assay//Anal. Biochem. - 1974. — Vol. 58. - P. 541-548.

[15] Kawabe J., Aizawa Y., Takehara N., Hasebe N., Kikuchi K. Glucose modifies the cross-talk between insulin and the beta-adrenergic signaling system in vascular smooth muscle cells//J. Hypertens. - 2000. - Vol. 18. - P. 1457-1464.

[16] Yang, S., Rembiesa, B., Bullesbach, E.E., Schwabe C.

[17] Relaxin receptors in mice: Demonstration of ligand binding in symphyseal tissues and uterine membrane fragments//Endocrinology. - 1992. - Vol. 130. - P. 179-185

[18] Greenbaum C.J. Insulin resistance in type 1 diabetes. Diabetes Metab. Res. Rev. — 2002. - Vol. 18. - C. 192-200.

[19] Fu L.X., Bergh C.H., Liang Q.M., Sjogren K.G., Xu X., Eriksson P., Hoebeke J., Hjalmarson A. Diabetes-induced changes in the Gi-modulated muscarinic receptor-adenylyl cyclase system in rat myocardium//Pharmacol. Toxicol. - 1994. - Vol. 75. - P. 186-193.

[20] Anand-Srivastava M.B., McNeill J. H., Yang X.P. Reversal of defective G-proteins and adenylyl cyclase/cAMP signal transduction in diabetic rats by vanadyl sulphate therapy//Mol. Cell Biochem. - 1995. - Vol. 153. - P. 113-119.

[21] Lin S., Kajimura M., Takeuchi K., Kodaira M., Hanai H., Nishimura M., Kaneko E. Alterations of GTP-binding proteins (Gsalpha and Gq/llalpha) in gastric smooth muscle cells from streptozotocin-induced and WBN/Kob diabetic rats//Dig. Dis. Sci. - 2000. - Vol. 15. - P. 1517-1524.

[22] Le Marchand-Brustel G. Molecular mechanism of insulin action in normal and insulin-resistant states//Exp. Clin. Endocrinol. Diabetes. - 1999. - Vol. 107. - P. 126-132.

[23] Le Roith D., Kim H., Fernandez A.M., Accili D. Inactivation of muscle insulin and IGFI receptors and responsiveness//Curr. Opin. Clin. Nutr. Metab. Care. - 2002. - Vol. 5. -P. 371-375.

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