Cam KinaseII

[peglem]

Trying to find implications of elevated camK levels from Cunningham study, I discovered that it is involved in the fight or flight response (at least as far as elevated heart rate) and so began looking for methods of lowering CamK levels....I came up empty on that. Any ideas or research for how those levels can be reduced?

[kim]

Peg,

 

We've probably been traveling down some of the same paths, but this in particular really caught my attention. Seems there's something important here. bolding mine

 

 

http://www.medicalnewstoday.com/articles/106098.php

 

Specifically, they showed that oxidation of two neighboring methionines -- sulfur-containing amino acids -- can sustain CaM kinase activity. Loss of these two methionines prevents activation by oxidation. They also found that they could return CaM kinase to its inactive state and inhibit heart cell death and dysfunction by using an enzyme called methionine sulfoxide reductase A (msrA), which reverses the methionine oxidation. Studies in worms, fruit flies and mice have shown that msrA increases lifespan, but, until now, the enzyme's targets in heart were unknown

 

Neurobiology of Disease

Methionine Sulfoxide Reductase A and a Dietary Supplement S-Methyl-L-Cysteine Prevent Parkinson's-Like Symptoms

 

Parkinson's disease (PD), a common neurodegenerative disease, is caused by loss of dopaminergic neurons in the substantia nigra. Although the underlying cause of the neuronal loss is unknown, oxidative stress is thought to play a major role in the pathogenesis of PD. The amino acid methionine is readily oxidized to methionine sulfoxide, and its reduction is catalyzed by a family of enzymes called methionine sulfoxide reductases (MSRs).

 

 

I have several more snippets of info....not sure anything is really helpful. I can spend hours going round and round with info like this and ultimately and get no where. I'm going to leave most of what I have here in case we have a "Buster" who can make any sense of it. I'm coping these as I had them saved.

 

http://www.medicalnewstoday.com/articles/141710.php

 

Shedding Light On Heart's 'Fight Or Flight' Response To Stress

 

Even for those without a heart condition, it's a peculiar feeling when your heart "races" in response to stress. That pacing change happens in part because of how the enzyme calcium/calmodulin-dependent protein kinase II (CaM kinase II) is called into action by the body's 'fight or flight' stress response,

http://www.sciencedirect.com/science?_ob=A...2c3bc2e7d82652a

 

Effect of diabetes on calcium/calmodulin dependent protein kinase-II from rat brain

 

The increase in CaM kinase II activity was more pronounced in the 12 weeks diabetic group. Insulin treatment of diabetic rats, resulted in recovery of enzyme activity near to control values from majority of the brain regions studied. The expression of α-subunit specific CaM kinase II correlates with the enzyme activity in the diabetic rat brain.

 

 

http://en.wikipedia.org/wiki/Ca2%2B/calmod..._protein_kinase

 

Function

Due to its ability for autophosphorylation, CaMK activity can outlast the intracellular calcium transient that is needed to activate it. In neurons, this property is important for the induction of synaptic plasticity. [1]Pharmacological inhibition of CaMKII blocks the induction of long-term potentiation. Upon activation, CaMKII phosphorylates postsynaptic glutamate receptors and thus changes the electrical properties of the synapse.

 

 

http://www.nature.com/npp/journal/v32/n12/full/1301378a.html

 

Chronic Antidepressants Induce Redistribution and Differential Activation of CaM Kinase II between Presynaptic Compartments

 

Changes in synaptic plasticity are involved in pathophysiology of depression and in the mechanism of antidepressants. Ca2+/calmodulin (CaM) kinase II, a protein kinase involved in synaptic plasticity, has been previously shown to be a target of antidepressants. We previously found that antidepressants activate the kinase in hippocampal neuronal cell bodies by increasing phosphorylation at Thr286, reduce the kinase phosphorylation in synaptic membranes, and in turn its phosphorylation-dependent interaction with syntaxin-1 and the release of glutamate from hippocampal synaptosomes

and

 

Furthermore, a large decrease in the level and phosphorylation of synapsin I located at synaptic membranes was consistent with the observed decrease of CaM kinase II. Overall, antidepressants induce a complex pattern of modifications in distinct subcellular compartments; at presynaptic level, these changes are in line with a dampening of glutamate release.

[kim]

Opps, forgot to include link for the above quote and probably the most important part!

 

 

http://www.jneurosci.org/cgi/content/abstract/27/47/12808

 

Parkinson's disease (PD), a common neurodegenerative disease, is caused by loss of dopaminergic neurons in the substantia nigra. Although the underlying cause of the neuronal loss is unknown, oxidative stress is thought to play a major role in the pathogenesis of PD. The amino acid methionine is readily oxidized to methionine sulfoxide, and its reduction is catalyzed by a family of enzymes called methionine sulfoxide reductases (MSRs).

and (bolding mine)

 

Furthermore, we demonstrate that one way to enhance the MSRA antioxidant system is dietary supplementation with S-methyl-L-cysteine (SMLC), found abundantly in garlic, cabbage, and turnips.

[peglem]

I googled cam kinase II autoimmunity and found many things that I couldn't make much sense out of, but this one seems a little more understandable to me...its about the role of camKII in the maturation of antigen presenting cells in the immune system. It seems significant to me, but can't get a good enough picture in my head for complete understanding:

 

http://www.jleukbio.org/cgi/content/full/78/6/1397

 

What does anybody who understands better than me, think?

[kim]

This is a mouse that lacks the gene all together, not where this pathway may be over taxed (a reminder to myself as much as to anyone else!). Michelle, if you're reading, I thought of Andrew (toe walking) as well as many children I have read about on autism bds. when I saw this.

 

http://www.pnas.org/content/98/23/12920.full

 

To gain a better understanding of the biological roles of MsrA in metabolism, we have created a strain of mouse that lacks the MsrA gene. Compared with the wild type, this mutant: (i) exhibits enhanced sensitivity to oxidative stress (exposure to 100% oxygen); (ii) has a shorter lifespan under both normal and hyperoxic conditions; (iii) develops an atypical (tip-toe) walking pattern after 6 months of age; (iv) accumulates higher tissue levels of oxidized protein (carbonyl derivatives) under oxidative stress; and (v) is less able to up-regulate expression of thioredoxin reductase under oxidative stress. It thus seems that MsrA may play an important role in aging and neurological disorders.

[kim]

http://www.emdbiosciences.com/html/cbc/pho..._Cam_kinase.htm

 

Many effects of Ca2+ are mediated by Ca2+/calmodulin (CaM)-dependent protein kinases (CaM kinases). CaM Kinases constitute a family of structurally related enzymes that include phosphorylase kinase, myosin light chain kinase, and CaM kinases I-IV. CaM Kinase II, one of the best-studied multifunctional enzymes, is found in high concentrations in neuronal synapses, and in some regions of the brain it may constitute up to 2% of the total protein content. Activation of CaM kinase II has been linked to memory and learning processes in the vertebrate nervous system. CaM Kinase II is a complex of about 12 subunits that exist in four differentially expressed forms (a, b, g, and d). In the inactive state there is a strong interaction between the inhibitory and catalytic domains of the enzyme. The binding of Ca2+/CaM allows the catalytic domain to phosphorylate the inhibitory domain. Once activated, CaM Kinase II retains significant activity even after the withdrawal of Ca2+, thereby prolonging the duration of kinase activity.

 

 

http://www.citeulike.org/group/5070/article/4163589

 

Abstract

Calcium/calmodulin-dependent protein kinase II (CaM Kinase II) is a known modulator of cardiac pathophysiology. The present review uniquely focuses on novel CaM Kinase II-mediated endothelial cell signalling which, under pathophysiological conditions, may indirectly modulate cardiac functions via alterations in endothelial or endocardial responses. CaM Kinase II has four different isoforms and various splicing variants for each isoform. The endothelial cell CaM Kinase II isoforms are sensitive to KN93 and a threonine 286-mutated inhibitory peptide. In macrovascular endothelial cells derived from aortas, CaM Kinase II mediates redox-sensitive upregulation of endothelial nitric oxide synthase (eNOS) gene expression by hydrogen peroxide (H2O2) and oscillatory shear stress, and a rapid activation of eNOS in response to bradykinin. In endothelial cells derived from lung microvessels, CaM Kinase II mediates barrier dysfunction, particularly when activated by thrombin. In brain capillary endothelial cells, CaM Kinase II lies upstream of voltage-gated potassium channels and hypoxia-induced cell swelling. In both macrovascular and microvascular endothelial cells, CaM Kinase II mediates actin cytoskeleton reorganization via distinct p38 MAPK/HSP27 and ERK1/2/MLCK signalling pathways, respectively. Although understanding of endothelium-specific CaM Kinase II signalling is nascent, data accumulated so far have demonstrated a potentially significant role of CaM Kinase II in endothelial cell pathophysiology. 10.1093/cvr/cvm010

 

 

excerpts

http://en.wikipedia.org/wiki/Endothelium

 

Endothelial tissue is a specialized type of epithelium tissue (one of the four types of biological tissue in animals). More specifically, it is simple squamous epithelium.

 

and

 

The foundational model of anatomy makes a distinction between endothelial cells and epithelial cells on the basis of which tissues they develop from and states that the presence of vimentin rather than keratin filaments separate these from epithelial cells.

 

and

 

In some organs, there are highly differentiated endothelial cells to perform specialized 'filtering' functions. Examples of such unique endothelial structures include the renal glomerulus and the blood-brain barrier.

 

 

http://www.ncbi.nlm.nih.gov/pubmed/1845417...ogdbfrom=pubmed

 

Negative regulation of multifunctional Ca2+/calmodulin-dependent protein kinases: physiological and pharmacological significance of protein phosphatases.Ishida A, Sueyoshi N, Shigeri Y, Kameshita I.

Laboratory of Molecular Brain Science, Graduate School of Integrated Arts and Sciences, Hiroshima University, Higashi-Hiroshima, Japan. aishida@hiroshima-u.ac.jp

 

Multifunctional Ca2+/calmodulin-dependent protein kinases (CaMKs) play pivotal roles in intracellular Ca2+ signaling pathways. There is growing evidence that CaMKs are involved in the pathogenic mechanisms underlying various human diseases. In this review, we begin by briefly summarizing our knowledge of the involvement of CaMKs in the pathogenesis of various diseases suggested to be caused by the dysfunction/dysregulation or aberrant expression of CaMKs. It is widely known that the activities of CaMKs are strictly regulated by protein phosphorylation/dephosphorylation of specific phosphorylation sites. Since phosphorylation status is balanced by protein kinases and protein phosphatases, the mechanism of dephosphorylation/deactivation of CaMKs, corresponding to their 'switching off', is extremely important, as is the mechanism of phosphorylation/activation corresponding to their 'switching on'. Therefore, we focus on the regulation of multifunctional CaMKs by protein phosphatases. We summarize the current understanding of negative regulation of CaMKs by protein phosphatases. We also discuss the biochemical properties and physiological significance of a protein phosphatase that we designated as Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP), and those of its homologue CaMKP-N. Pharmacological applications of CaMKP inhibitors are also discussed. These compounds may be useful not only for exploring the physiological functions of CaMKP/CaMKP-N, but also as novel chemotherapies for various diseases

[kim]

This post was copied from another thread.....

 

I had posted some info on a thread that Peglem started regarding CaMKs. It seemed where heart injury or arrythmia's were concerned that methionine was involved with elevated CaMK. One article said something like "the loss of two neighboring methionines," which I didn't understand at all. It said if these methionines were "lost," that CaM kinase would return to it's normal state.

 

Recently I ran across a diagram that I thought might explain it. It shows where calmodulin, after undergoing transformation by the addition of calcium, has "unmasked," or exposed methionine. Some of the other articles on that thread seemed to show where something called MSRA (S-Methyl-L-Cysteine), would protect cells against damage from oxidation (ok I'm getting lost...have to go find the thread and read this AGAIN) but one study talked about MSRA being found abundantly in garlic, beets, and cabbage. This study was in regards to Parkinson's, which made me think about the tremors that some seem to experience. I, myself had had periods of irregular heartbeats for years, and my oldest son has mentioned it a few times during illness and also a "tremory," feeling. I"m taking orgainic garlic caps right now and continuing to look for new info in this area. Just wondered if anyone thought this was as interesting as I do!

 

Here's the diagram of calmodulin

 

http://www.pdb.org/pdb/static.do?p=educati...th/pdb44_2.html

 

I think these are the key articles from that thread with one that I just found thrown in. I had these saved, so I'll have to read them myself to see if they are the ones that I think they are

 

http://www.medicalnewstoday.com/articles/106098.php

Study Identifies New Mechanism Linking Activation Of Key Heart Enzyme And Oxidative Stress

 

 

http://www.jneurosci.org/cgi/content/abstract/27/47/12808

Methionine Sulfoxide Reductase A and a Dietary Supplement S-Methyl-L-Cysteine Prevent Parkinson's-Like Symptoms

 

 

http://www.ncbi.nlm.nih.gov/pubmed/20374422

Dopamine D receptor function is compromised in the brain of the methionine sulfoxide reductase A knockout mouse

[kim]

http://jn.nutrition.org/cgi/content/full/134/1/149

 

Balb/cA mice were used to study the in vivo effect of N-acetyl cysteine, S-allyl cysteine, S-ethyl cysteine, S-methyl cysteine and S-propyl cysteine, all derived from garlic, on glutathione (GSH) concentration and catalase and glutathione peroxidase (GPX) activities in plasma, kidney and liver.

 

 

Increased dopamine initially with a decrease later....1 mouse year approx 34 human years?

 

 

Free Radic Biol Med. 2008 Jul 15;45(2):193-200. Epub 2008 Apr 15.

 

MsrA knockout mouse exhibits abnormal behavior and brain dopamine levels.

Oien DB, Osterhaus GL, Latif SA, Pinkston JW, Fulks J, Johnson M, Fowler SC, Moskovitz J.

 

Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA.

 

Abstract

Oxidative stress can cause methionine oxidation that has been implicated in various proteins malfunctions, if not adequately reduced by the methionine sulfoxide reductase system. Recent evidence has found oxidized methionine residues in neurodegenerative conditions. Previously, we have described elevated levels of brain pathologies and an abnormal walking pattern in the methionine sulfoxide reductase A knockout (MsrA(-/-)) mouse. Here we show that MsrA(-/-) mice have compromised complex task learning capabilities relative to wild-type mice. Likewise, MsrA(-/-) mice exhibit lower locomotor activity and altered gait that exacerbated with age. Furthermore, MsrA(-/-) mice were less responsive to amphetamine treatment. Consequently, brain dopamine levels were determined. Surprisingly, relative to wild-type mice, MsrA(-/-) brains contained significantly higher levels of dopamine up to 12 months of age, while lower levels of dopamine were observed at 16 months of age. Moreover, striatal regions of MsrA(-/-) mice showed an increase of dopamine release parallel to observed dopamine levels. Similarly, the expression pattern of tyrosine hydroxylase activating protein correlated with the age-dependent dopamine levels. Thus, it is suggested that dopamine regulation and signaling pathways are impaired in MsrA(-/-) mice, which may contribute to their abnormal behavior. These observations may be relevant to age-related neurological diseases associated with oxidative stress.

[trggirl]

Awesome thread!! Thank you!