Nitric oxide (NO) has emerged as a novel regulator of several ovarian events, such
as ovulation, steroidogenesis, and apoptotic cell death. The NO synthases (NOS) are
a family of enzymes that catalyze the oxidation of L-arginine to NO and L-citrulline.
Three main isozymes exist in mammals that are regulated by distinct genes: a
constitutive neuronal NOS (nNOS or NOS1), an endotoxin- and cytokine-inducible
NOS (iNOS or NOS2), and a constitutive endothelial NOS (eNOS or NOS3).
NCBI Summary:
The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a reactive free radical, which acts as a biologic mediator in several processes, including neurotransmission, and antimicrobial and antitumoral activities. In the brain and peripheral nervous system, nitric oxide displays many properties of a neurotransmitter, and has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. This protein is ubiquitously expressed, with high level of expression in skeletal muscle. Multiple transcript variants that differ in the 5' UTR have been described for this gene but the full-length nature of these transcripts is not known. Additionally, alternatively spliced transcript variants encoding different isoforms (some testis-specific) have been found for this gene.[provided by RefSeq, Feb 2011]
General function
Enzyme
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Cellular localization
Cytoskeleton
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Ovarian function
Ovulation
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NO-mediated regulation of GLUT by T3 and FSH in rat granulosa cells. Tian Y et al. (2017) Thyroid hormones (THs) are important for normal reproductive function. Although 3,5,3'-triiodothyronine (T3) enhances follicle-stimulating hormone (FSH)-induced preantral follicle growth and granulosa cells development in vitro, little is known about the molecular mechanisms regulating ovarian development via glucose. In this study, we investigated whether and how T3 combines with FSH to regulate glucose transporter protein (GLUT) expression and glucose uptake in granulosa cells. Here, we present evidence that T3 and FSH co-treatment significantly increased GLUT-1/GLUT-4 expression, and translocation in cells, as well as glucose uptake. These changes were accompanied by upregulation of NOS3 expression, total NOS and NOS3 activity and NO content in granulosa cells. Furthermore, we found that activation of the mTOR and PI3K/Akt pathway is required for the regulation of GLUT expression, translocation, and glucose uptake by hormones. We also found that L-arginine (L-arg) up-regulated GLUT-1/GLUT-4 expression and translocation, which were related to increased glucose uptake, however, these responses were significantly blocked by L-NAME. In addition, inhibiting NO production attenuated T3 and FSH-induced GLUT expression, translocation, and glucose uptake in granulosa cells. Our data demonstrate that T3 and FSH co-treatment potentiates cellular glucose uptake via GLUT upregulation and translocation, which are mediated through the activation of the mTOR/PI3K/Akt pathway. Meanwhile, NOS3/NO are also involved in this regulatory system. These findings suggest that GLUT is a novel mediator of T3 and FSH-induced follicular development.//////////////////
Expression regulated by
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Ovarian localization
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Follicle stages
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Phenotypes
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:Klein SL, et al 1998 reported impaired ovulation in mice with targeted deletion of the neuronal
isoform of nitric oxide synthase.
Ovulation was assessed in wild-type (WT) and nNOS-/- female
mice by examining the number of ovarian rupture sites and number of oocytes
recovered from the oviducts following mating or exposure to exogenous
gonadotropins (i.e., 5 IU pregnant mares serum gonadotropin [PMSG] and 5 IU
human chorionic gonadotropin [hCG]). Ovulatory efficiency was determined as
the number of ovulated oocytes per number of ovarian rupture sites. To examine
whether ovulatory deficits in nNOS-/- mice were due to alternations in central
mechanisms, plasma luteinizing hormone (LH) concentrations were assessed in
WT and nNOS-/- mice that were challenged with 25 ng of gonadotropin-releasing
hormone (GnRH). To determine whether ovulatory deficits in nNOS-/- mice were
due to local ovulation processes, nerves innervating the reproductive tract of WT
and nNOS-/- females were examined for the presence of nNOS protein.
There were substantial fertility deficits in nNOS-/- female mice; the
nNOS-/- mice had fewer oocytes in their oviducts following spontaneous and
gonadotropin-stimulated ovulation. Pituitary responsiveness to exogenous GnRH
challenge was intact in nNOS-/- mice. Dense nNOS protein staining was observed
in nerves innervating the reproductive tracts of WT mice. The
reproductive deficits in nNOS-/- females are most likely due to alternations in the
transfer of oocytes from the ovaries to the oviducts during ovulation. These results
suggest that defects in neuronally derived NO production may contribute to female
infertility.
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - non-ovarian defect Comment:Robert Gyurko, et al reported the deletion of Exon 6 of the Neuronal Nitric Oxide Synthase Gene in Mice Results in Hypogonadism and Infertility.
The first line of mice deficient in neuronal NO synthase (referred to herein as KN1 mice) reproduce normally. However, residual neuronal NO synthase (nNOS) activity is detected in KN1 mice due to the expression of ? and -nNOS splice variants. The authors generated a new line of nNOS knockout mice (KN2) lacking exon 6, which codes for the heme-binding domain of nNOS. KN2 mice are viable, but mated homozygotes do not produce litters, indicating that either one or both sexes are infertile. Male KN2 mice show decreased gonad weights, but sperm counts are normal. KN2 males do not display mating behavior, and consequently do not leave vaginal plugs when housed with wild-type (WT) females. KN2 females show decreased ovary weight, and histology reveals decreased corpus luteum counts. RIAs show that KN2 males have decreased plasma FSH, whereas KN2 females have increased levels of plasma LH and increased hypothalamic GnRH content. Experimental ovarian transplantation suggests that central, rather than ovarian, processes are influenced by nNOS, as KN2 ovaries ovulate at near-normal rates under WT hormonal control, whereas WT ovaries transplanted into KN2 mice have decreased ovulation rates.