Calcium Dependent NOS Induction by Sex Hormones: Estrogen
Reporter and Curator: Sudipta Saha, Ph.D.
Nitric oxide (NO) synthases (NOSs) constitute a family of isozymes that catalyze the oxidation of L-arginine to NO and citrulline. First identified in the vascular endothelium, NO synthesis has subsequently been shown to play important roles in:
- the regulation of vascular and gastrointestinal tone,
- in cell-mediated cytotoxicity against bacteria and tumors, and
- in a variety of central and peripheral nervous system activities.
NOSs can be divided into three functional classes based on their sensitivity to calcium.
- The cytokine- or bacterial product-inducible isoenzyme iNOS binds calmodulin tightly at resting intracellular calcium concentrations.
- The constitutive forms, isozymes eNOS (originally described in endothelial cells) and
- nNOS (originally described in neuronal tissue), bind calmodulin in a reversible and calcium-dependent fashion.
The mechanisms by which their synthesis is controlled are unknown. The cDNA species encoding the rat, mouse, and human nNOS, the human and bovine eNOS, and iNOS from several species and cell types have been cloned and sequenced. The three human isozymes characterized to date are distinct, with their deduced protein sequences showing only 50-60%o amino acid identity. nNOS, which in rats and humans localizes to neurons in the central and peripheral nervous system and colocalizes with NADPHdiaphorase activity, has also been shown to be widely distributed in several non-neuronal tissues including human skeletal muscle.
It had been thought that both nNOS and eNOS were purely constitutive enzymes, although studies suggest eNOS may be induced by shear stress. Studies demonstrate that these NOSs can be induced in several tissues during pregnancy and in nonpregnant female and male animals by estradiol and that in skeletal muscle it is accompanied by an increase in NOS-specific mRNA.
Evidences emerging from various laboratories showed that there is an increase in the release of NO from the vasculature during pregnancy. Furthermore, treatment of pregnant animals at the end of gestation with tamoxifen reduced NOS activity in the cerebellum, an organ where tamoxifen acts as a pure estrogen-receptor antagonist. Thus, the increase in calcium-dependent NOS activity during pregnancy is mediated by estrogen. This conclusion is supported by the fact that treatment of nonpregnant females and male animals with estradiol also increased calcium-dependent NOS activity in all tissues studied.
Interestingly, testosterone treatment also increased cerebellar NOS activity without affecting other tissues. However, testosterone may increase brain NOS by directly binding estrogen receptors as has been reported. Furthermore, the cerebellum was the only tissue in the male to respond to a 5-day course of estradiol, suggesting that it may have a larger number and/or a greater availability of estrogen receptors than other tissues. In addition, the brain is rich in aromatase, which converts testosterone into estradiol. This, together with the observation that progesterone does not induce NOS, indicates that the induction of both nNOS and eNOS is specific for estrogen and not a characteristic of all sex steroids. These experiments do not exclude the possibility that the addition of progesterone might modify the estradiol effect.
The increases in NOS activity are the result of augmented enzyme synthesis (enzyme induction) since they are accompanied by increases in the specific mRNAs for both eNOS and nNOS. It is not, however, possible to tell whether the increases in mRNA are caused by an upregulation of mRNA synthesis (transcriptional induction) or decreased mRNA breakdown.
Although calcium-dependent NOS activity was increased by estradiol in tissues obtained from both female and male guinea pigs, a longer duration of treatment was necessary in the male. The most likely explanation for this observation is that the number or availability of estrogen receptors is initially too low in most tissues of the male and requires a period of estrogen priming. Although other factors may play a role, the duration of exposure may well explain the observation that the effect of pregnancy on NOS-specific mRNA is greater than estradiol alone.
The observation that estradiol induces calcium-dependent NOSs has several important implications:
- An increase in release of NO from the endothelium would decrease vascular tone and contractility, events that are characteristic in pregnancy.
- Heterogeneity among tissue endothelium regarding the effects of estrogen on basal NO release could explain the selective redistribution of maternal cardiac output to organs important for a successful pregnancy.
- Consistent with this possibility is the observation that the effect of pregnancy on endothelium-derived NO is greatest in the uterine artery, followed by the mesenteric artery and then renal arteries.
- An alternative hypothesis to explain the adaptation of smooth muscle to pregnancy is that it is caused by prostacyclin. Prostacyclin is increased during pregnancy and contributes to the observed reduced contractility of the ovine uterine artery to angiotensin II.
However, estradiol does not increase the synthesis of prostacyclin by the endothelium, nor does inhibition of prostacyclin synthesis prevent the effects of pregnancy on smooth muscle. In addition, both the incidence of esophageal reflux and the gastrointestinal transit time are increased during pregnancy. Although this phenomenon has previously been attributed to a direct effect of progesterone, NO is a powerful dilator of the gastrointestinal smooth muscle. If the increase in NOS activity observed in the esophagus applies to the bowel, enhanced NO might be the mechanism underlying both increased esophageal reflux and transit time.
The biological signifcance of an estradiol-dependent increase in the NOS in the central nervous system is of great interest and deserves further investigation. Furthermore, an estradiol-mediated increase in NOS in the vasculature could be the mechanism whereby premenopausal women are protected from coronary artery disease since increased NOS may slow the development of atherosclerosis and reduce the contractile response to acute thrombosis. Finally, the induction of calcium-dependent NOS enzymes by estradiol suggests that the present classification of this family of enzymes into constitutive and inducible types needs to be revised, since eNOS and nNOS enzymes at least are both constitutive and inducible.
Source References:
http://www.ncbi.nlm.nih.gov/pubmed?term=Calcium%20dependent%20NOS%20induction%20by%20sex%20hormones
Other research published on Nitric Oxide on this Scientific Web Site include the following:
Nitric Oxide in bone metabolism July 16, 2012
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Nitric Oxide production in Systemic sclerosis July 25, 2012
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Nitric Oxide Signalling Pathways August 22, 2012 by
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The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure August 20, 2012
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Nitric Oxide: The Nobel Prize in Physiology or Medicine 1998 Robert F. Furchgott, Louis J. Ignarro, Ferid Murad August 16, 2012
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Calcium dependent NOS induction by sex hormones: Estrogen
Curator: S. Saha, PhD, October 3, 2012
http://pharmaceuticalintelligence.com/2012/10/03/calcium-dependent-nos-induction-by-sex-hormones/
Nitric Oxide and Platelet Aggregation
Author V. Karra, PhD, August 16, 2012
http://pharmaceuticalintelligence.com/2012/08/16/no-and-platelet-aggregation/
Curator: Aviva Lev-Ari, PhD, July 16, 2012
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Dr. Saha,
This is a GREAT post which demonstrates the relationships between pregnancy physiological changes, mRNA functions, levels of NO in pregnancy, eNOS induction, levels of Estrogen and Calcium dependent NOS, in addition, the specifics of brain anatomic involvement in these complex processes. Protacyclin and Progesterone, their involvement with NO, eNOS — are very revealing.
I was edified in a very big way about these relationships and the explanations provided to the Female physiology during pregnancy and for the pre-menopausal phase roles of NO, eNOS. With the implications of post-menapausal decrease in levels of estrogen.
The comparison of Male and Femal differences in regards to above mentioned relationships is very important for medical management of diseases by gender.
Post delivery, women have a high risk for disseminated intravascular coagulopathy (DIC), related to coagulation cascade, now it is presented to have been impacted by NO, eNOS as well.
It is a great pleasure to read this post and see relationships recently discovered to exist and how very needed they are for explanation of human physiological changes along the Life Span, in addition to Gender role played and been a must to be used in planning the disease management in either sex.
I made editorial changes to the structure of the post to improve readability and emphasize key processes at work. I added Estrogen to the title for specificity. Please used these structural modification as an example for future posts.
Thank you again, a great curator on our Team.
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette