Developmentally acquired PKA localisation in mouse oocytes and embryos

Webb, Rachel J.; Tinworth, Lorna; Thomas, Geraint M. H.; Zaccolo, Manuela; Carroll, John

doi:10.1016/j.ydbio.2008.01.045

Cited by 26 publications

(17 citation statements)

References 43 publications

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“…Therefore, it is possible that cAMP is able to readily diffuse throughout the oocyte cytoplasm prior to LH stimulation to activate intracellular PKAs. In support of this, the catalytic subunit of PKA is present both in the plasma membrane and throughout the cytoplasm (Brown et al 2002, Webb et al 2008.…”

Section: Discussionmentioning

confidence: 89%

“…On the other hand, b 1 -ARs generate cAMP signals capable of diffusing over 10 mm throughout large adult ventricular cardiomyocytes even in the absence of PDE inhibitors (Nikolaev et al 2006). AKAPs have been identified in mouse oocytes (Brown et al 2002, Kovo et al 2006, Newhall et al 2006) and the RI-and RII-type PKAs are tethered in the plasma membrane and the cytoplasm respectively (Brown et al 2002, Newhall et al 2006, Webb et al 2008. However, PDE activity is kept low in oocytes by cGMP, which is produced in the Figure 6 Inhibiting endocytosis with dynasore increases cAMP levels in oocytes.…”

Section: Discussionmentioning

confidence: 99%

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Endocytosis in the mouse oocyte and its contribution to cAMP signaling during meiotic arrest

Lowther¹,

Nikolaev²,

Mehlmann³

2011

Reproduction

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Mammalian oocytes are arrested at prophase I of meiosis until a preovulatory surge of LH stimulates them to resume meiosis. Prior to the LH surge, high levels of cAMP within the oocyte maintain meiotic arrest; this cAMP is generated in the oocyte through the activity of the constitutively active, G s -coupled receptor, G-protein-coupled receptor 3 (GPR3) or GPR12. Activated GPRs are typically targeted for desensitization through receptor-mediated endocytosis, but a continuously high level of cAMP is needed for meiotic arrest. The aim of this study was to examine whether receptor-mediated endocytosis occurs in the mouse oocyte and whether this could affect the maintenance of meiotic arrest. We found that constitutive endocytosis occurs in the mouse oocyte. Inhibitors of receptor-mediated endocytosis, monodansylcadaverine and dynasore, inhibited the formation of early endosomes and completely inhibited spontaneous meiotic resumption. A red fluorescent protein-tagged GPR3 localized in the plasma membrane and within early endosomes in the oocyte, demonstrating that GPR3 is endocytosed. However, overexpression of G-protein receptor kinase 2 and b-arrestin-2 had only a modest effect on stimulating meiotic resumption, suggesting that these proteins do not play a major role in GPR3 endocytosis. Inhibition of endocytosis elevated cAMP levels within oocytes, suggesting that there is an accumulation of GPR3 at the plasma membrane. These results show that endocytosis occurs in the oocyte, leading to a decrease in cAMP production, and suggest that there is a balance between cAMP production and degradation in the arrested oocyte that maintains cAMP levels at an appropriate level during the maintenance of meiotic arrest.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Endocytosis in the mouse oocyte and its contribution to cAMP signaling during meiotic arrest

Lowther¹,

Nikolaev²,

Mehlmann³

2011

Reproduction

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“…Optical indicators based on Förster resonance energy transfer (FRET) Russwurm et al, 2007;Willoughby and Cooper, 2008) are ideal for this purpose. These sensors have been used in mouse oocytes (Webb et al, 2002;Webb et al, 2008), although not in oocytes within antral follicles. The sensor used in those studies, comprising fluorescent catalytic and regulatory subunits of PKA, has the disadvantage of inhibiting meiotic progression (Webb et al, 2002), probably because it elevates PKA activity (Goaillard et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte

et al. 2009

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Mammalian oocytes are arrested in meiotic prophase by an inhibitory signal from the surrounding somatic cells in the ovarian follicle. In response to luteinizing hormone (LH), which binds to receptors on the somatic cells, the oocyte proceeds to second metaphase, where it can be fertilized. Here we investigate how the somatic cells regulate the prophase-to-metaphase transition in the oocyte, and show that the inhibitory signal from the somatic cells is cGMP. Using FRET-based cyclic nucleotide sensors in follicleenclosed mouse oocytes, we find that cGMP passes through gap junctions into the oocyte, where it inhibits the hydrolysis of cAMP by the phosphodiesterase PDE3A. This inhibition maintains a high concentration of cAMP and thus blocks meiotic progression. LH reverses the inhibitory signal by lowering cGMP levels in the somatic cells (from ~2 μM to ~80 nM at 1 hour after LH stimulation) and by closing gap junctions between the somatic cells. The resulting decrease in oocyte cGMP (from ~1 μM to ~40 nM) relieves the inhibition of PDE3A, increasing its activity by ~5-fold. This causes a decrease in oocyte cAMP (from ~700 nM to ~140 nM), leading to the resumption of meiosis.

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“…It is generally accepted that the Akinase anchoring proteins (AKAP), which contain a targeting domain for specific subcellular localizations, translocate PKA to some intracellular compartments by binding to PKA-Rs. There are more than 40 members in the AKAP family [30], and it has been reported that at least AKAP1, AKAP2, and AKAP7c are expressed in mouse oocytes [15,31,32]. Among these AKAPs, AKAP1 has been reported to be essential for meiotic maturation involved in the translocation of PKA-R2 to the mitochondria [15].…”

Section: Discussionmentioning

confidence: 99%

Analyses of the Involvement of PKA Regulation Mechanism in Meiotic Incompetence of Porcine Growing Oocytes1

Nishimura

Fujii

Kanô

et al. 2012

Biology of Reproduction

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Mammalian growing oocytes (GOs) lack the ability to resume meiosis, although the molecular mechanism of this limitation is not fully understood. In the present study, we cloned cDNAs of cAMP-dependent protein-kinase (PKA) subunits from porcine oocytes and analyzed the involvement of the PKA regulation mechanism in the meiotic incompetence of GOs at the molecular level. We found a cAMP-independent high PKA activity in GOs throughout the in vitro culture using a porcine PKA assay system we established, and inhibition of the activity by injection of the antisense RNA of the PKA catalytic subunit (PKA-C) induced meiotic resumption in GOs. Then we examined the possibility that the amount of the PKA regulatory subunit (PKA-R), which can bind and inhibit PKA-C, was insufficient to suppress PKA activity in GOs because of the overexpression of two PKA-Rs, PRKAR1A and PRKAR2A. We found that neither of them affected PKA activity and induced meiotic resumption in GO although PRKAR2A could inhibit PKA activity and induce meiosis in cAMP-treated full-grown oocytes (FGOs). Finally, we analyzed the subcellular localization of PKA subunits and found that all the subunits were localized in the cytoplasm during meiotic arrest and that PKA-C and PRKAR2A, but not PRKAR1A, entered into the nucleus just before meiotic resumption in FGOs, whereas all of them remained in the cytoplasm in GOs throughout the culture period. Our findings suggest that the continuous high PKA activity is a primary cause of the meiotic incompetence of porcine GOs and that this PKA activity is not simply caused by an insufficient expression level of PKA-R, but can be attributed to more complex spatial-temporal regulation mechanisms.

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Developmentally acquired PKA localisation in mouse oocytes and embryos

Cited by 26 publications

References 43 publications

Endocytosis in the mouse oocyte and its contribution to cAMP signaling during meiotic arrest

Endocytosis in the mouse oocyte and its contribution to cAMP signaling during meiotic arrest

Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte

Analyses of the Involvement of PKA Regulation Mechanism in Meiotic Incompetence of Porcine Growing Oocytes1

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