A large number of hormones, neurotransmitters, and other signaling substances that bind to
G-protein-coupled cell-surface receptors have their signals converge at one sole second messenger,
cAMP.
An increasing number of cAMP kinase isozymes, consisting of homo- or heterodimers of R subunits (RIalpha, RIbeta, RIIalpha, RIIbeta) with associated catalytic subunits (C alpha, Cbeta, Cgamma), have been identified. The various cAMP kinase isozymes display distinct biochemical properties, and the
heterogeneous subunits reveal cell-specific expression and differential regulation at the level of
gene transcription, mRNA stability, and protein stability in response to a wide range of hormones and
other signaling substances. The existence of a number of anchoring proteins specific to either RIIalpha or
RIIbeta, and which localize cAMP kinase II isozymes toward distinct substrates at defined subcellular loci,
strongly supports the idea that specific functions can be assigned to the various isozymes. The catalytic alpha subunit requires phosphorylation for full activity.
NCBI Summary:
cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the cAMP-dependent protein kinase, which transduces the signal through phosphorylation of different target proteins. The inactive kinase holoenzyme is a tetramer composed of two regulatory and two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. The protein encoded by this gene is one of the regulatory subunits. This subunit can be phosphorylated by the activated catalytic subunit. It may interact with various A-kinase anchoring proteins and determine the subcellular localization of cAMP-dependent protein kinase. This subunit has been shown to regulate protein transport from endosomes to the Golgi apparatus and further to the endoplasmic reticulum (ER). [provided by RefSeq, Jul 2008]
General function
Intracellular signaling cascade
Comment
Jahnsen T, et al. reported the purification and characterization of hormone-regulated isoforms of the regulatory subunit of type II
cAMP-dependent protein kinase from rat ovaries.
An active protein kinase A (PKA) is involved in meiotic arrest of rat growing oocytes. Kovo M et al. Reinitiation of meiosis in meiotically competent, fully grown mammalian oocytes is governed by a fall in intraoocyte cAMP concentrations and the subsequent inactivation of protein kinase A (PKA). A similar reduction in intraoocyte cAMP concentrations in growing, meiotically incompetent rat oocytes not leading to resumption of meiosis, questions the involvement of PKA in the regulation of meiosis at this early stage of oocyte development. We examined the possibility of whether PKA activity maintains growing oocytes in meiotic arrest and further explored the mode of activation of PKA under conditions of relatively low cAMP concentrations. Our experiment demonstrated that inactivation of PKA stimulates growing rat oocytes to resume meiosis, and elevates the activity of their maturation-promoting factor (MPF). We also found that the expressions of type I and type II regulatory subunits (RI and RII) of PKA are higher in growing and fully grown oocytes, respectively. In addition, we revealed that the common 1:1 ratio between the regulatory (R) and catalytic (C) subunits of PKA is apparently not abrogated and, in accordance PKA activity in growing oocyte - cell extract is fully dependent on cAMP. Finally, we identified in growing oocytes, the A kinase anchoring protein (AKAP) 140, which was previously depicted in fully grown oocytes. We conclude that an active PKA prevents growing oocytes from resuming meiosis. Our findings further suggest that relatively high abundance of the PKAI isoform and/or its subcellular compartmentalization, through interaction with AKAP140, could possibly account for the high basal PKA activity at relatively low intraoocyte cAMP concentrations.
Expression regulated by
FSH, LH, Steroids
Comment
Ratoosh SL, et al. reported the hormonal regulation of the synthesis and mRNA content of the regulatory subunit of cyclic
AMP-dependent protein kinase type II in cultured rat ovarian granulosa cells. These studies indicate that in
cultured rat granulosa cells the synthesis of RII51 and the content of its mRNA are selectively increased
by estradiol and cAMP in a time- and dose-dependent manner.
Kurten RC, et al reported the identification and characterization of the GC-rich and cyclic adenosine 3',5'-monophosphate
(cAMP)-inducible promoter of the type II beta cAMP-dependent protein kinase regulatory subunit
gene.
Ovarian localization
Oocyte, Cumulus, Granulosa, Theca, Luteal cells
Comment
Analyses of the Involvement of PKA Regulation Mechanism in Meiotic Incompetence of Porcine Growing Oocytes. Nishimura T et al. Mammalian growing oocytes (GOs) lack an ability to resume meiosis, although the molecular mechanism of this limitation has not been 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 a molecular level. First, we found a cAMP-independent high PKA activity in GOs throughout the in vitro culture using the 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 bound and inhibited PKA-C, was insufficient to suppress PKA activity in GOs by overexpression of two PKA-Rs, PRKAR1A and PRKAR2A. We found that neither of them affected PKA activity and induced meiotic resumption in GO, while 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 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 FGO, whereas all of them remained at 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.
Hedin L et al , used cDNA probes specific for the regulatory (R) subunits [RII51; (mol wt, 51,000) and RI (mol wt, 49,000)]
and a catalytic (C alpha) subunit of cAMP-dependent protein kinases to analyze the hormonal
regulation, tissue distribution, and content of mRNAs for these kinase subunits in the rat ovary. Filter
hybridization assays demonstrated that mRNA specific for RII51 increased in both thecal and granulosa
cells of preovulatory (PO) follicles, then declined precipitously in both cell types
within 7 h after an ovulatory dose of hCG and remained low in corpora lutea. Solution hybridization
assays demonstrated that the concentration of RII51 mRNA increased 6-fold from 20
molecules/granulosa cell in H rats to 120 molecules/cell in H rats treated with estradiol and FSH (HEF).
In thecal cells of small antral (SA), PO, and luteinizing follicles, changes
in the content of mRNA for RI and C alpha kinase subunits showed a pattern similar to that for RII51.
However, in granulosa cells, mRNA specific for RI and C alpha was highest in SA follicles, declined in
PO follicles, and remained unchanged during luteinization. These results indicate that the content of RII51 mRNA is hormonally
regulated in both thecal cells and granulosa cells during follicular development and luteinization. Low
concentrations of gonadotropins increase RII51 mRNA, whereas an ovulatory dose of hCG causes
mRNA for RII51 to decrease rapidly. In granulosa cells, induction of mRNA for RII51, but not that for RI
and C alpha is induced by the actions of estradiol and FSH, and involves increased transcription of the
RII51 gene.
Follicle stages
Primordial, Secondary, Antral, Preovulatory, Corpus luteum
Comment
Arraztoa JA, et al 2005 reported the identification of genes expressed in primate primordial oocytes.