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General Comment |
NCBI Summary:
This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin. Mutation of this gene results in Brunner syndrome. This gene has also been associated with a variety of other psychiatric disorders, including antisocial behavior. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Jul 2012]
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Comment |
Dopamine in human follicular fluid is associated with cellular uptake and metabolism-dependent generation of reactive oxygen species in granulosa cells: implications for physiology and pathology. Saller S 2013 et al.
STUDY QUESTION
Is the neurotransmitter dopamine (DA) in the human ovary involved in the generation of reactive oxygen species (ROS)?
SUMMARY ANSWER
Human ovarian follicular fluid contains DA, which causes the generation of ROS in cultured human granulosa cells (GCs), and alterations of DA levels in follicular fluid and DA uptake/metabolism in GCs in patients with polycystic ovary syndrome (PCOS) are linked to increased levels of ROS.
WHAT IS KNOWN ALREADY
DA is an important neurotransmitter in the brain, and the metabolism of DA results in the generation of ROS. DA was detected in human ovarian homogenates, but whether it is present in follicular fluid and plays a role in the follicle is not known.
STUDY DESIGN, SIZE AND DURATION
We used human follicular fluid from patients undergoing in vitro fertilization (IVF), GCs from patients with or without PCOS and also employed mathematical modeling to investigate the presence of DA and its effects on ROS.
PARTICIPANTS/MATERIALS, SETTING AND METHODS
DA in follicular fluid and GCs was determined by enzyme-linked immunosorbent assay. GC viability, apoptosis and generation of ROS were monitored in GCs upon addition of DA. Inhibitors of DA uptake and metabolism, an antioxidant and DA receptor agonists, were used to study cellular uptake and the mechanism of DA-induced ROS generation. Human GCs were examined for the presence and abundance of transcripts of the DA transporter (DAT; SLC6A3), the DA-metabolizing enzymes monoamine oxidases A/B (MAO-A/B) and catechol-O-methyltransferase and the vesicular monoamine transporter. A computational model was developed to describe and predict DA-induced ROS generation in human GCs.
MAIN RESULTS AND ROLE OF CHANCE
We found DA in follicular fluid of ovulatory follicles of the human ovary and in GCs. DAT and MAO-A/B, which are expressed by GCs, are prerequisites for a DA receptor-independent generation of ROS in GCs. Blockers of DAT and MAO-A/B, as well as an antioxidant, prevented the generation of ROS (P < 0.05). Agonists of DA receptors (D1 and D2) did not induce ROS. DA, in the concentration range found in follicular fluid, did not induce apoptosis of cultured GCs. Computational modeling suggested, however, that ROS levels in GCs depend on the concentrations of DA and on the cellular uptake and metabolism. In PCOS-derived follicular fluid, the levels of DA were higher (P < 0.05) in GCs, the transcript levels of DAT and MAO-A/B in GCs were 2-fold higher (P < 0.05) and the DA-induced ROS levels were found to be more than 4-fold increased (P < 0.05) compared with non-PCOS cells. Furthermore, DA at a high concentration induced apoptosis in PCOS-derived GCs.
LIMITATIONS, REASONS FOR CAUTION
While the results in IVF-derived follicular fluid and in GCs reveal for the first time the presence of DA in the human follicular compartment, functions of DA could only be studied in IVF-derived GCs, which can be viewed as a cellular model for the periovulatory follicular phase. The full functional importance of DA-induced ROS in small follicles and other compartments of the ovary, especially in PCOS samples, remains to be shown.
WIDER IMPLICATIONS OF THE FINDINGS
The results identify DA as a factor in the human ovary, which, via ROS generation, could play a role in ovarian physiology and pathology. The results obtained in samples from women with PCOS suggest the involvement of DA, acting via ROS, in this condition.
STUDY FUNDING/COMPETING INTERESTS
This work was supported by a grant from DFG MA1080/17-3 and in part MA1080/19-1. There are no competing interests.
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Total monoamine oxidase activity in the hypothalamus, ovary and uterus of rats with an extreme number of ovarian corpora lutea. Ivanisevic-Milovanovic OK, et al analyzed total MAO activity in the hypothalamus, uterus and ovary in adult rats, having an extreme number of corpora lutea (hyperluteinized ovaries) resulting from the mechanical lesions in the posterior hypothalamic region of neonatal rats. Total MAO activity in the hypothalamus (30.21 +/- 1.53 pmol/mg tissue/min) and uterus (3.16 +/- 0.61 pmol/mg tissue/min) of rats with hyperluteinized ovaries did not show a significant difference as compared to that of intact controls (31.09 +/- 1.72 and 2.90 +/- 0.40 pmol/mg tissue/min, respectively). In contrast, in the ovaries of hyperluteinized rats, total MAO activity (21.16 +/- 1.70 pmol/mg tissue/min) was significantly higher (p<0.01) when compared to that of intact controls (13.61 +/- 1.30 pmol/mg tissue/min). The increased MAO activity in the hyperluteinized ovaries may be attributed to the increased number of transformed and accumulated corpora lutes as a consequence of diminished luteolysis.
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Comment |
Monoamine oxidase-A is highly expressed by the human corpus luteum of pregnancy. Takao Y et al. To investigate the physiological characteristics of the corpus luteum (CL) of pregnancy, we raised a monoclonal antibody (mAb), HCL-4, against human luteal cells obtained from CL of pregnancy. The affinity-purified antigen from human CL of pregnancy or placenta using HCL-4 was a 61kD protein. The partial amino acid sequence of the antigenic protein was identical to that of human monoamine oxidase-A (MAO-A, EC1.4.3.4). MAO-A has been shown to catabolize catecholamines that were reported to regulate luteal function in CL and vasoconstriction in various organs. Immunohistochemistry using HCL-4 mAb showed that MAO-A was intensely expressed on large luteal cells and moderately expressed on small luteal cells in the CL of pregnancy. In the CL of menstrual cycle, MAO-A was weakly detected on large luteal cells but not detected at all on small luteal cells. Western blotting analysis confirmed the high expression of MAO-A in CL of pregnancy. Northern blot analysis also showed the expression of MAO-A mRNA in human CL, and showed that its expression was higher in CL of pregnancy than in CL of menstrual cycle. The increased expression of MAO-A on CL of pregnancy suggests the contribution of MAO-A to the function of CL of pregnancy.
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