The overall objective of this proposal is to understand the molecular mechanisms by which hormones influence uterine smooth muscle contraction and relaxation.
Aim 1 will elucidate the contributions of the oxytocin receptor (OTR) intracellular loops to the specificity of interaction and activation of GTP-binding proteins (G-proteins). Receptor chimeras, site-specific receptor mutants, and the ability of over expressed intracellular loop peptides to inhibit coupling will be used to examine OTR/G-protein interactions.
Aim 2 will define the mechanisms by which cAMP inhibits G-protein stimulated phosphatidylinositol turnover in myometrium. The effect of phosphorylation of specific components on activity in the cell and in reconstituted artificial membranes will be explored and the effect of cell permeable protein kinase A anchor inhibitors on the ability of relaxin to inhibit G-protein-coupled phospholipase C will be determined.
Aim 3 will determine the contribution of cAMP-mediated inhibition of G-protein stimulated phosphatidylinositol turnover in various stages of pregnancy in the rat. The ability of CPT-cAMP to inhibit OT-stimulated PI turnover during pregnancy in relation to expression and coupling of elements required to elevate cAMP will be determined.
Aim 4 will determine the relationship between changes in ion channel activity, Ca release and Ca sequestration, and oxytocin-stimulated Ca(i) transients and oscillations in myometrial cells. The effect of perturbing these mechanisms on time-dependent changes in OT-stimulated Ca(i) transients and Ca(i) oscillations in single cells will be determined. Understanding these mechanisms is critical to the design of modalities to manage premature labor and dysfunctional labor, conditions which pose significant health risks for both mother and child.
|Kim, Paul Y; Zhong, Miao; Kim, Yoon-Sun et al. (2012) Long chain polyunsaturated fatty acids alter oxytocin signaling and receptor density in cultured pregnant human myometrial smooth muscle cells. PLoS One 7:e41708|
|Ku, Chun-Ying; Murtazina, Dilyara A; Kim, Yoon-Sun et al. (2010) Changes in rat myometrial plasma membrane protein kinase A are confined to parturition. Reprod Sci 17:696-704|