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Reporter: Aviva Lev-Ari, PhD, RN

 

Press Release

13 January, 2013

Hebrew University study finds key mechanism in calcium regulation.  The finding is important element in road towards development of new drugs for neurodegenerative diseases

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All living cells keep their cellular calcium concentration at a very low level. Since a small increase in calcium can affect many critical cellular functions (an elevated calcium concentration over an extended period can induce cell death), powerful cellular mechanisms ensure that calcium concentration quickly returns to its low level.

It is known that impairments of cellular calcium regulation underlie almost all neurodegenerative diseases. For example, age-related loss of calcium regulation was shown to promote cell vulnerability in Alzheimer’s disease.

In a study recently published in the Journal of Neuroscience, Hebrew University of Jerusalem researchers, along with others from Israel and the US, presented their findings of a previously undescribed cellular mechanism which is essential for keeping cellular calcium concentration low. 
This mechanism operates together with other already characterized mechanisms.

Dr. Shirley Weiss and Prof. Baruch Minke of the Hebrew University’s Institute of Medical Research Israel-Canada (IMRIC) and the Edmond and Lily Safra Center for Brain Sciences (ELSC) characterized this mechanism using photoreceptor cells of the fruit fly, which is a powerful model for studying basic biological processes. 

They found that a protein-designated calphotin (a calcium buffer) operates by sequestering elevated calcium concentration. Genetic elimination of calphotin led to a light-induced rise in cellular calcium for an abnormally extended time, leading to retinal photoreceptor degeneration in the fruit flies.

The researchers stress that this kind of research, leading to a better understanding of the fundamental mechanisms underlying cellular calcium regulation, is critical for the development of new drugs and treatments for neurodegenerative diseases. 

SOURCE:

http://www.huji.ac.il/cgi-bin/dovrut/dovrut_search_eng.pl?mesge135806850705872560

 

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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

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

http://goo.gl/eVXFh

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