Multiple cAMP Phosphodiesterases Act Together to Prevent Premature Oocyte Meiosis and Ovulation

Abstract

Luteinizing hormone (LH) acts on the granulosa cells that surround the oocyte in mammalian preovulatory follicles to cause meiotic resumption and ovulation. Both of these responses are mediated primarily by an increase in cyclic adenosine monophosphate (cAMP) in the granulosa cells, and the activity of cAMP phosphodiesterases (PDEs), including PDE4, contributes to preventing premature responses. However, two other cAMP-specific PDEs, PDE7 and PDE8, are also expressed at high levels in the granulosa cells, raising the question of whether these PDEs also contribute to preventing uncontrolled activation of meiotic resumption and ovulation. With the use of selective inhibitors, we show that inhibition of PDE7 or PDE8 alone has no effect on the cAMP content of follicles, and inhibition of PDE4 alone has only a small and variable effect. In contrast, a mixture of the three inhibitors elevates cAMP to a level comparable with that seen with LH. Correspondingly, inhibition of PDE7 or PDE8 alone has no effect on meiotic resumption or ovulation, and inhibition of PDE4 alone has only a partial and slow effect. However, the fraction of oocytes resuming meiosis and undergoing ovulation is increased when PDE4, PDE7, and PDE8 are simultaneously inhibited. PDE4, PDE7, and PDE8 also function together to suppress the premature synthesis of progesterone and progesterone receptors, which are required for ovulation. Our results indicate that three cAMP PDEs act in concert to suppress premature responses in preovulatory follicles.

Thrombospondin 1 (THBS1) Promotes Follicular Angiogenesis, Luteinization, and Ovulation in Primates

“…Cumulus expansion has been described as a necessary prerequisite for resumption of oocyte meiosis (50). However, additional pathways promoting oocyte meiotic progression may be independent of cumulus expansion (51, 52). While much remains to be learned, our studies point to a critical role for thrombospondins, and in particular THBS1, as a paracrine regulator of follicular angiogenesis and ovulation in primates.…”

Follicle-stimulating hormone and luteinizing hormone increase Ca2+ in the granulosa cells of mouse ovarian follicles1

“…4B,C,D). The peak concentration of LH in the serum during the mouse reproductive cycle is about 1 nM [48,49], but 330 10 nM is the minimum concentration of ovine LH needed to cause meiotic resumption in all follicles under our experimental conditions [7], perhaps related to use of LH from a different species.…”

“…Both FSH and LH stimulate the G s /cAMP/protein kinase A (PKA) pathway [2], and pharmacological activation of this pathway is, with a few exceptions, sufficient to fully mimic responses to FSH [1,2,4] and LH [2,[5][6][7]. Correspondingly, many of the FSH-and LH-stimulated 30 responses are inhibited by inhibition of PKA [1,2], although non-specificity of some commonly used PKA inhibitors [8] leaves open the question of whether FSH and LH signaling through non-PKA pathways may also be important.…”

“…The 1 nM concentration of FSH required to stimulate a rise in Ca 2+ correlates well with the concentration of FSH needed to optimally stimulate follicular development in our culture system. In this system, 0.3 nM FSH causes ~80% of follicles to acquire the ability to resume meiosis in response to LH, whereas 1 nM FSH causes 100% of follicles to become LH responsive [7]. During the reproductive cycle,…”

Germline Variants in Phosphodiesterase Genes and Genetic Predisposition to Pediatric Adrenocortical Tumors

“…Chronic lymphocytic leukemia cells exhibit increased PDE7B expression [11]; PDE5 is strongly expressed in glioblastoma multiforme [12] and colon cancer [13], and glioma cells overexpress one or more isoforms of PDE4 [14]. Furthermore, several PDE isoforms are present in granulosa cells as well as in oocytes in preovulatory follicles of the mammalian ovary regulating the meiotic cell cycle [15]. Additionally, many PDEs are expressed in cells of the spermatogenic pathway where they may regulate sperm motility [16], and PDE5 is expressed in the contractile tissues of the male excurrent duct and accessory glands where its increased activity contributes to erectile dysfunction [16].…”