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.
Highlights
In higher primates, during non-pregnant cycles, it is indisputable that circulating LH is essential for maintenance of corpus luteum (CL) function
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
The quantitative RT-PCR (qPCR) analysis of LH/CGR expression at different stages of luteal phase revealed that the mRNA expression increased progressively to reach maximum at the late stage CL (2.4 ± 0.4, 3.3 ± 0.5 and 6.9 ± 1.2 ng/ml at early, mid and late stage, respectively Figure 1A)
Summary
In higher primates, during non-pregnant cycles, it is indisputable that circulating LH is essential for maintenance of corpus luteum (CL) function. Several studies have described the phenomenon of activated GPCRs to crosstalk with or transactivate tyrosine kinase receptor signaling [16,17], and extensive studies in mouse Leydig tumor cells have demonstrated involvement of Src family of kinases (SFKs) in modulation of LH/CG responsiveness, and thereby regulation of Leydig cell function [18,19,20,21]. Eventhough the precise mechanism by which LH/CGR signaling causes activation of these kinases and the functional consequences of their activation remains to be determined, SFKs might have an important role in the regulation of CL function, perhaps by modulation of LH/CG responsiveness, during the late luteal phase of non-fertile cycles. Studies are essential to identify other signaling pathways to further delineate intraluteal processes to discern those that are critical to the control of luteal function and its life span
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