Identification of phosphodiesterase 9A as a cyclic guanosine monophosphate–specific phosphodiesterase in germinal vesicle oocytes: a proposed role in the resumption of meiosis

Abstract

Objective To identify a cGMP-specific phosphodiesterase (PDE) in non-human primate germinal vesicle (GV) oocytes and establish a proposed effect on oocyte maturation through preliminary experiments in mouse GV oocytes. Design Controlled non-human primate and rodent experiments. Setting Academic research institution. Animals Rhesus macaques and B6/129F1 mice. Interventions Rhesus macaques were stimulated with FSH to collect GV oocytes and cumulus for gene expression analysis. Female mice were stimulated with PMSG to collect GV oocytes. Main Outcome Measures PDE transcript expression in primate GV oocytes and cumulus cells. Fluorescence polarization (FP) measurements of PDE3A activity. Spontaneous resumption of meiosis in mouse GV oocytes. Results Five PDE transcripts were detected in Rhesus GV oocytes, only PDE9A was cGMP-specific. FP assays indicated cGMP has an inhibitory effect on PDE3A while the PDE9 inhibitor, BAY73-6691, did not. Similarly, BAY73-6691, had little effect on preventing spontaneous maturation in oocytes, but did augment the inhibitory effects of cGMP. Inclusion of 0µM (control), 10µM, 100µM, and 1 mM BAY73-6691 significantly increased the proportion of mouse oocytes maintaining GV arrest in the presence of the cGMP analog 8-Br-cGMP at: 100µM (8.8%, 11.4%, 18.8%, and 28%), 500µM (21.1%, 38.1%, 74.5%,and 66.5%), and 1 mM (57.8%, 74.5%, 93.9%, and 94.0%) respectively, when P<0.05. Conclusions PDE9 is a cGMP-specific hydrolyzing enzyme present in primate oocytes, and PDE9 antagonists augment the inhibitory effect of cGMP during spontaneous in vitro maturation of GV mouse oocytes.

Cyclic guanosine monophosphate does not inhibit gonadotropin-induced activation of mitogen-activated protein kinase 3/1 in pig cumulus-oocyte complexes

“…Moreover, the cGMP analogues are probably hydrolyzed in the COCs by cGMP-specific phosphodiesterases, the activity of which may be affected by FSH. In support of these assumptions, an inhibitor of phosphodiesterase 9A (PDE9A) enhanced the negative effect of 8-Br-cGMP on mouse oocyte meiotic resumption [ 45 ]. As mentioned previously, PDE5A and PDE6C, upregulated in response to gonadotropin, may also hydrolyze the cGMP analogues [ 17 ].…”

C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling

“…PDE9A can be detected in all tissues, including the heart [15] . In the past few years, PDE9A has been regarded as a therapeutic target for the treatment of various diseases [16][17][18] . A PDE9A inhibitor, PF-04447943(PF-7943), has been reported to elevate central cGMP levels in the brain and cerebrospinal fluid of rodents and has been confirmed to be well tolerated by humans in clinical trials [16] .…”

Role of Cyclic Nucleotide Phosphodiesterases During Meiotic Resumption From Diplotene Arrest in Mammalian Oocytes

“…PDE3A is a major isoform expressed in the oocytes [Richard et al, ; Shitsukawa et al, ; Conti, ] and it is restricted to the oocyte only [Tsafriri et al, ; Sasseville et al, ]. The PDE8A and PDE9A are reported in bovine and primate oocytes, respectively [Sasseville et al, ; Hanna et al, ]. PDE3A accounts for 80% of the total PDE activity while PDE8A contributes to remaining 20% in bovine oocyte [Bilodeau‐Goeseels, ].…”

“…The PDE9A isoform has been reported in several mammalian species [Kocabas et al, ; Hanna et al, ]. PDE9A specifically hydrolyzes cGMP in GV stage immature primate oocytes [Hanna et al, ]. Due to this ability, PDE9A may be used as a potential candidate for the removal of cGMP‐mediated inhibition.…”

“…Due to this ability, PDE9A may be used as a potential candidate for the removal of cGMP‐mediated inhibition. PDE9A is greatly expressed in human M‐II arrested oocytes [Kocabas et al, ; Hanna et al, ]. A possibility exists that PDE9A may be a dominant cGMP‐specific degrading enzyme in the oocyte.…”