Curator/Author: Aviral Vatsa PhD, MBBS
Nitric oxide is one of the smallest molecules involved in physiological functions in the body. It is a diatom and thus seeks formation of chemical bonds with its targets rather than structure-function configuration of say protein receptors. Nitric oxide can exert its effects principally by two ways:
- Direct
- Indirect
Direct actions, as the name suggests, result from direct chemical interaction of NO with its targets e.g. with metal complexes, radical species. These actions occur at relatively low NO concentrations (<200 nM)
Indirect actions result from the effects of reactive nitrogen species (RNS) such as NO2 and N2O3. These reactive species are formed by the interaction of NO with superoxide or molecular oxygen. RNS are generally formed at relatively high NO concentrations (>400 nM)
Credits: Nitric Oxide: Biology and Pathobiology By Louis J. Ignarro
Although it can be tempting for scientists to believe that RNS will always have deleterious effects and NO will have anabolic effects, this is not entirely true as certain RNS mediated actions mediate important signalling steps e.g. thiol oxidation and nitrosation of proteins mediate cell proliferation and survival, and apoptosis respectively. As depicted in the figure above, NO concentration determines the action it exerts on different proteins. This is highlighted in the following examples from different studies:
- Cells subjected to NO concentration between 10-30 nM were associated with cGMP dependent phosphorylation of ERK
- Cells subjected to NO concentration between 30-60 nM were associated with Akt phosphorylation
- Concentration nearing 100 nM resulted in stabilisation of hypoxia inducible factor-1
- At nearly 400 nM NO, p53 can be modulated
- >1μM NO, it nhibits mitochondrial respiration
Besides the concentration, duration of NO exposure also determines how proteins respond to NO. Hence proteins can be ‘immediate’ responders or ‘delayed’ responders. The response can be either ‘transient’ (short lived) or ‘sustained’ (prolonged). Different proteins fall into these different categories. These are not rigid categories rather a functional ‘classification’.
Endogenously generated NO concentration ranges from 2 nM as in endothelial cell to >1 μM in a fully activated macrophage. This wide range, along with the unique chemical reactivity of NO offers immense versatility to the physiological effects that it can exert in different cellular milieu in the body.
In addition to the concentration-dependent effects, other factors that determine the local cellular/tissue milieu add to the complexities involved with signal transduction undertaken by NO. These factors are
- rate of NO production
- diffusion distance
- rates of consumption
- reactivity of RNS with molecular targets.
These kinetic determinants play vital role in physiological functions and disease states.
Although it is not possible to detail the modes of modulation of biological functions by NO in a short post, but I hope the post gives a taste of the intricacies involved with NO functions and that there are various parameters that determine the exact role of NO in a biological milieu.
Sources
http://www.pnas.org/content/101/24/8894.short
http://onlinelibrary.wiley.com/doi/10.1002/ijc.22336/full
http://cancerres.aacrjournals.org/content/67/1/289.short
http://www.sciencedirect.com/science/article/pii/S0005272806000417
This is fascinating. It opens up many questions to be explored.
Thanks for your comment. Indeed NO is fascinating signalling molecule and it is probably one of the most important cross roads in our physiological systems where many systems criss cross.
A viral, thank you for this fundamental post. One in a series of posts you plan to deliver on this fascinating RNS.
Please consider to present the actual molecular structure and several interactions. Please consider to have a post on NO and vascular smooth muscle, NO and nerve cells, NO and peptide, NO and endothelium and NO vasodilatation, thus decrease of blood pressure.
May I chart here a ROAD MAP for the forthcoming series of posts in our NO research category. A viral, you are our Category OWNER, you may coordinate with other EAW that wish to submit posts.
You pursue your own research agenda, I wish to make sure that in few months all the following topics are covered, thus, Other EAW may wish to contribute. To foster collaboration and efficiency any EAW who wish to work on the following topics will coordinate with, Aviral.
Of special interest to us are the following:
NO and glycolysis, NO and inhibition of platelet aggregation, NO oxidental stress and CAD, Nitrergic innervation of GU tract, NO nitrergic neurodegeneration and diabetes, NO and Hypoxia, NO macrophage and cytotoxicity, effects of statins on endothelial NO, NOS inhibition and Septic shock, NO and mitochondrial function, NO and atherosclerosis, Interaction of NO and prostacyclin in vascular endothelium, NO and BP, NO and vassal wall, Calcium, NO and myocardium, Calcium dependent NOS induction by sex hormones, NO hypoxia reticulum stress and Mitochondrial respiration
Please send feedback
I am very happy to work with other EAW on any topic pertaining to NO. Please do get in touch if anyone is interested in combining efforts to come up with multifocused posts with NO a as common ground.
OK. I’ll get in sync shortly.
You sent me an e-mail last week with 6 previous posts that I have for working into the piece I had posted. They are all dealing with stem cell modification and with NO, even by Aviral. Let’s get more clarity on this because I have gotten it ready to do so. There is about 40% references in the material.
I do have other topics I’ll want to go into. It can wait. This is a big undertaking. Think about spreading it out some with the idea that we want to get a broad readership.
I believe that Arival has his plan for NO, he should have the freedom to do that since he had initiated this Researh Category.
I chartered the map above for all EAW that wish to join efforts and write on NO. We must have the topics in the road map been covered because Aviva believes that THESE NO related topic WILL bring many readers to our site,
Larry, I requested you to focus on Stem Cell and Cardiac repair post MI, having to develop an Integrative Approach derived from the work of Dr Saha and Aviva’s work in vascular biology and molecular cardiology.
What are the relations of NO and Stem Cells?
The link is Nebivolol — A drug to stimulate NO production to Augmet cEPCs in human blood thus reducing Macrovascular events — that was one of the contributions of Part II of my research.
Larry, we need you to take the lead on Stem Cells and MI with Aviva and Dr, Saha. This is a huge topic and a bigger Unbrella than NO. We plan to integrate NO under the Umbrella.
At present time, may I suggest to have TWO tracts,
– one on NO per the Road Map above plus the plan that Aviral has for this Category.
– Second on Stem Cells and Cardiac Repair: Larry to integrate work of Dr. Saha and Aviva’s
hello, i think very insteresting the work with this reactive molecule. Please, check my profile If you need a posdoctoral position. I have very years working with free radicals.
thanks a lot
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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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