Involvement of Src family of kinases and cAMP phosphodiesterase in the luteinizing hormone/chorionic gonadotropin receptor-mediated signaling in the corpus luteum of monkey

Abstract

BackgroundIn higher primates, during non-pregnant cycles, it is indisputable that circulating LH is essential for maintenance of corpus luteum (CL) function. On the other hand, during pregnancy, CL function gets rescued by the LH analogue, chorionic gonadotropin (CG). The molecular mechanisms involved in the control of luteal function during spontaneous luteolysis and rescue processes are not completely understood. Emerging evidence suggests that LH/CGR activation triggers proliferation and transformation of target cells by various signaling molecules as evident from studies demonstrating participation of Src family of tyrosine kinases (SFKs) and MAP kinases in hCG-mediated actions in Leydig cells. Since circulating LH concentration does not vary during luteal regression, it was hypothesized that decreased responsiveness of luteal cells to LH might occur due to changes in LH/CGR expression dynamics, modulation of SFKs or interference with steroid biosynthesis.MethodsSince, maintenance of structure and function of CL is dependent on the presence of functional LH/CGR its expression dynamics as well as mRNA and protein expressions of SFKs were determined throughout the luteal phase. Employing well characterized luteolysis and CL rescue animal models, activities of SFKs, cAMP phosphodiesterase (cAMP-PDE) and expression of SR-B1 (a membrane receptor associated with trafficking of cholesterol ester) were examined. Also, studies were carried out to investigate the mechanisms responsible for decline in progesterone biosynthesis in CL during the latter part of the non-pregnant cycle.Results and discussionThe decreased responsiveness of CL to LH during late luteal phase could not be accounted for by changes in LH/CGR mRNA levels, its transcript variants or protein. Results obtained employing model systems depicting different functional states of CL revealed increased activity of SFKs [pSrc (Y-416)] and PDE as well as decreased expression of SR-B1correlating with initiation of spontaneous luteolysis. However, CG, by virtue of its heroic efforts, perhaps by inhibition of SFKs and PDE activation, prevents CL from undergoing regression during pregnancy.ConclusionsThe results indicated participation of activated Src and increased activity of cAMP-PDE in the control of luteal function in vivo. That the exogenous hCG treatment caused decreased activation of Src and cAMP-PDE activity with increased circulating progesterone might explain the transient CL rescue that occurs during early pregnancy.

Multiple Pathways Mediate Luteinizing Hormone Regulation of cGMP Signaling in the Mouse Ovarian Follicle1

“…This may be due to release of a pre-existing pool of growth factors via activation of an ecto protease, as suggested by the sensitivity to GM6001, or via an intracellular mechanism by which the EGFR kinase activity is being activated. The Src kinase, for instance, can phosphorylate and activate EGFR [42]. After 30-60 min, de novo production of EGF-like growth factors contributes to propagation of the LH effect throughout the follicle, as documented by the further increase in EGFR phosphorylation at 2 h [30].…”

Alteration of glycan structures by swainsonine affects steroidogenesis in bovine luteal cells

“…Because N-glycans on LHR are important for its binding affinity [30], alteration in glycan structures on LHR by SW is possibly involved in alteration of binding affinity followed by suppression of progesterone production. Because LH stimulates the expression of various proteins involved in progesterone production by LSCs, such as StAR [38,42] and SR-BI [43][44][45], we further investigated the effects of SW on StAR and SR-BI protein expressions. Steroidogenic acute regulatory protein and SR-BI protein expressions stimulated by LH treatment were suppressed by a pretreatment with SW in cultured LSCs (Fig.…”

Role of intraluteal and intrauterine prostaglandin signaling in LH-induced luteolysis in pregnant rats

“…Immunoblot analysis of the total protein lysates from CL tissue was carried out as per the procedures reported previously (Kunal et al ., 2012). Table 1 contains the list of antibodies used in the immunoblotting analysis.…”