In trying to prove XMRV link to interestitial cystitis I'm finding great info

Notes on IC and ATP


Studies have shown that when bladder epithelial cells are stretched they release ATP. In the bladders of people with interstitial cystitis, more extracellular ATP is released than in control patients.

Quote: (BMJ August 8th, 2009: 339:337-342)
(IC bladder uroepithelial cells released significantly higher concentrations of ATP (adenosine triphosphate) than control biopsies suggesting that ATP plays an important role in this syndrome. An investigation of cultured bladder epithelial cells showed that such cells have an abnormal, much higher concentration of ATP. This higher concentration of ATP decreases the ability of the bladder wall to conduct (channel) potassium ions which again indicates impaired potassium ion conduction is part of the pathology of interstitial cystitis.

Studies on ME/CFS have shown deficient ion channelopathy to be part of the pathology of ME/CFS. Some studies about ME/CFS and potassium conduction attribute this flaw to abnormal mitochondrial gene expression.

The BMJ article cited says studies on IC showing ATP increase and changes in potassium conduction as also resulting from abnormal gene expression.

I suggest the issue of ATP, potassium ion channelopathy as being the result of XMRV. Idiosyncratic production of ATP and its components such as purinergic receptors, ATP- binding cassettes (ABCs) and or ABC transporters is well documented in many other autoimmune diseases and can be fully attributed to the source of most IC symptoms.

I hypothesize these abnormalities are the result the presence of XMRV in interstitial cystitis, and occur through many different mechanisms, including viral mimicry and others.

The hypothesis that XMRV likely cause of significantly high release of ATP in bladder urothelial cells is supported by observed defects in ATP-binding cassette transporters, where XMRV viral mimicry of proteins is likely to have occurred..

About ATP Binding Cassettes
ATP-binding cassette transporters are members of a protein superfamily that is one of the largest and oldest proteins.
ABC transporters are transmembrane proteins that utilize the energy of adenosine triphosphate (ATP) hydrolysis to carry out certain biological processes including the translocation of various substrates across membranes and non-transport related processes such as translation of RNA and DNA repair. ABCs transport a wide variety of substrates across extra and intracellular membranes, including metabolic products, lipids and sterols, and drugs. Proteins are classified as ABC transporters based on the sequence and organization of their ATP-binding cassette (ABC) domain(s). ABC transporters are involved in tumor resistance, cystic fibrosis, bacterial multi drug resistance and a range of other inherited human diseases.

One of these diseases is Pseudoxanthoma Elasticum (PXE), a hereditary connective tissue disease in which proteoglycans have altered properties. In pseudoxanthoma elasticum there are abnormalities which show some relevance to interstitial cystitis. Both diseases show a relationship with sulfated glycosaminoglycans. The only difference is that in PXE, an inherited genetic defect in an ATP-binding cassette transporter identified as ABCC6/MRP6

The idea that ABCC6/MRP6 is the cause of PXE was tested in 2003 in Italy.
Proteoglycan metabolism in PXE was studied by Francesca Maccari, Dealba Gheduzzi and Nicola Vopi at the University of Modena, in Modena, Italy.

In this study, the researchers measured sulfated glycosaminoglycans in the urine of people with PXE, people carrying the disease and healthy controls. Sulfated glycosaminoglycans are what compose the mucosal lining of the human bladder, known as the GAG layer. The GAG layer is deficient in IC patients because the bladder epithelial cells which secrete GAG become compromised and cease to serve their function.

The glycosaminoglycans this study on PXE tested for were chondriotin sulfate disaccharide and heparan sulfate disaccharide. Note also that to treat interstitial cystitis, heparin sulfate is instilled into the bladder to augment the defective GAG layer. In Canada and elsewhere outside the U.S., chondriotin sulfate has been used with even better results than heparin sulfate as a bladder instillation, to help IC patients in those places.

In PXE 34% less of the polysaccharides were detected in the urine of PXE individuals, than controls or unaffected carriers of the genetic defect.

It is worth noting that the commonality between IC and PXE patients may extend beyond glycosaminoglycans being abnormally low. On the revealing of the genome for XMRV, a comparison of what human proteins the XMRV retrovirus mimics finds a link between the virus and ABC transporters.

A retrovirus is different from normal viruses. Normal viruses only have their DNA transcribed into RNA in the host, and the RNA is then translated into a protein. A retrovirus functions in a different way, which more adeptly inserts its genome into human DNA. Retroviruses have their RNA reverse-transcribed into DNA, which is then integrated into the hosts genome and then undergoes the usual transcription and translation processes to express the genes carried by the virus.

How this relates to the issue of XMRV and autoimmune diseases, its speculated that XMRV creates proteins which mimic those in the human body. The idea is that the fake DNA created by the virus initiates a response from the human immune system. Some believe that the human immune system becomes confused from the retroviral proteins which mimic its own proteins. This leads to the unending attack from the body on its own tissue.

There is an ATP-binding cassette associated with the viral mimicry of XMRV infection. It is called ABCC9:

It is known as EAW96452.1. This is an ATP-binding cassette of the subfamily C (CFTR/MRP), member 9, isoform ABCC9. XMRV GAG- PRO-POL was found to mimic the natural properties of this ABC.

Note that ABCC6 in PXE where altered levels of glycosaminoglycans is very closely related to ABCC9. Both of these ATP-binding cassettes are of the subfamily MRP.


However, a link between this possibly compromised ATP binding cassette know as ABCC9 and interstitial cystitis goes further than its proximity in nature to ABCC6.
Here is what the genome mapping project says about ABCC9

ABC proteins transport various molecules across extra and intra cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein is thought to form ATP sensitive potassium channels in cardiac, skeletal and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel modulating subunit of the extra pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated in cardiomyopathy dilated type 10. Alternative splicing results in multiple transcript variants.

Now we go back to the idea the BMJ article expressed; the idea that come IC pain comes from inability for the bladder epithelial cells in IC patients to channel potassium ions. Also issues involving dysfunctional bladder smooth muscle activity parallel a possible defect in ABCC9 as a causative agent in IC symptoms. Bladder spasms and pelvic floor muscle issues become clearer when the idea of viral mimicry of ABCC9, or other ABCs.

Potassium channeling function by ABCC9 also alludes to the co-morbidity of mitral valve prolapse in interstitial cystitis patients. This too is another trait common to both IC and CFS/ME. Furthermore, defective cassette binders have been linked to the lack of energy proliferation in the bodies of CFS patients. Potassium channeling has also been linked to the pain of fibromyalgia.

The studies of Dr. Light bind the idea that a defect in receptors in the muscle fiber of fibromyalgia patientsreceptors which detect levels of ATP used or not used by the body which is part of the role which ABCs and or ATP sensors like purinergic receptors play in the pathology of that disease.

This makes good enough sense to me. Looking at the many studies which show the prevalence of extracellular ATP in both human and feline IC patients, and furthermore, studies which demonstrate a clear link between extracellular ATP and pain in the human bladders support the idea of ATP being at the root of IC abnormalities.

Source: Augmented Extracellular ATP Signaling in Bladder Urothelial Cells from Patients with Interstitial Cystitis Study by Yan Sun and Toby C. Chai, Division of Urology, Department of Surgery, University of Maryland School of Medicine.
http://apjcell.physiology.org/content/290/1/C27.full


Studies regarding extracellular ATP causing pain in human bladders extend beyond IC research. There was a study performed in Sweden demonstrating that extracellular ATP and the purinergic receptors P2Y are responsible for the inflammatory response in human bladders exposed to the E coli bacteria. Or to put in simple terms, ATP and purinergic receptors which bind to ATP are responsible for the pain and inflammation in the common urinary tract infection.

Bladder stretching itself also causes the bladder epithelial cells to excrete ATP. Studies have ranged from hypothesizing that extracellular ATP serves a role as a signaling mechanism in the human body, where its release upon stretching the human bladder generates the feeling and urge to go. I blame the inability of ABC transporters to serve their role in transporting substrates through intra and extracellular membranes as being part of why some substances irritate IC bladders and cause no sensation of pain in people with normal bladder tissue.

I attribute the experience of interstitial cystitis as being largely dependent upon defective ATP-binding cassette behavior.

I suggest exercise works as an IC therapy because it uses up the extracellular ATP.

I will show proof for my argument in referring to a study which show that extracellular ATP is responsible for other IC anomalies, including the defect where tryptophan in IC patients is broken down into kynurenine over serotonin and melatonin.

The indoleamine 2,3, dioxygenase pathway is the formal name for the modification of tryptophan into various other chemicals.

Here is a study proving that extracellular ATP effects the maturation of human dendritic cells (immune cells), affecting the indoleamine pathway:
Source: Thrombospondin and indoleamine 2,3 dioxygenase are major targets of extracellular ATP in human dendritic cells. Frdrick Marteu, Nathalie Suarez Gonzalez, David Communi, Michel Goldman, Jean-Marie Boeynaems, and Didler Communi. http://bloodjournal.hematologylibrary.org/content/10612/3860.full

This article states:

Extracellular adenosine triphosphate affects the maturation of human dendritic cells, mainly by inhibiting T-helper (Th 1) cytokines, promoting Th2 cytokines and modulating the expression of costimulatory molecules. In this study we report that adenosine triphosphate can induce immunosuppression through its own action on DCs, defining a new role for extracellular nucleotides. Microarray analysis of ATP-stimulated human DCs revealed an inter alia a drastic up-regulation of 2 genes encoding mediators involved in immunosuppression: thrombospondin-1 and indoleamine.."

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It is known that bladder stretching causes cells to release ATP. This is one way physical changes alone can alter bladder surface biochemistry.

Furthermore, the amounts of extracellular ATP becomes more prevalent upon mechanical stretch can be reduced by chemicals already present in the bladder. In a study by Sun Y and Chai TC at the Division of Urology at the University of Maryland School of Medicine, both heparin sulfate and dimethyl sulphoxide (DMSO) reduce the higher levels of stretch activated ATP release in the bladders of people with interstitial cystitis.

The idea supported by the results of this study is that bladder epithelial cells (bladder urothelial cells or BUCs) are able to detect levels of ATP and rely upon ATP as a chemical messenger of sorts.

Another thing which stresses the importance of studying the role of ATP in interstitial cystitis is that ATP plays a major role in generating the disease symptoms in other autoimmune disorders:

So you ME/CFS people don't feel left out of this research, know that this is oh, so relevant to solving your problem too. Again, I'm finding good material:

Purinergic Irregularities and Autoimmune Disease

Source: Review: Potential Retrovirus Causal Paths in CFS and FM Rev 2. Laurence G. Felker, Reno, NV (775) 852-9326.

Disregulated immune, endocrine and neurological systems are well known. Adenosine triphosphate (ATP) processing has been clearly shown to be abnormally regulated in CFS and a test is now available which correlates severity of the condition with ATP processing. Evidence also exists which shows other abnormalities in purine regulation contribute to this condition. If extracellular ATP, adenosine diphosphate (ADP) and adenosine monophosphate (AMP) are elevated while adenosine (ADO) is deficient, then multiple effects will occur. Nociceptive input via the P2X3 receptors is elevated. Endocrine disruption can occur. Cellular energy levels are lower accounting for fatigue. Since ADO promotes sleep, its lower levels may account for the sleep disturbances found in CFS.

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Here are some of my notes:

ATP Cassette Binders, Purinergic Receptors; Role in pathogenesis of Autoimmune and Relation to XMRV Infection

ABC cassettes are related to XMRV infection
ABCE1 ATP-binding cassette, subfamily E (OABP), member 1, [Homo sapiens]
Also known as RNASEL1; RNASELI, RLI, OABP, ABC38
The protein encoded by this gene is a member of the subfamily of ATP binding cassette transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This protein is a member of the OABP subfamily. Alternatively referred to as the RNase L inhibitor, this protein functions to block the activity of ribonuclease L. Activation of ribonuclease L leads to inhibition of protein synthesis in the 2-5A/RNasel L system, the central pathway for viral interferon action. Two transcript variants encoding for the same protein have been found for this gene.

Genomic context:
Chromosome: 4; Location 4q31

ABCC9 ATP-binding cassette, subfamily, C (CFTR/MRP), member 9 [homo sapiens]
Also known as SUR2, ABC 37, CMD1O; FLJ36852
Te protein encoded by this gene is a member of the superfamily of ATP-binding cassette transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinctive subcategories (ABC1, MDR/TAP, ALD, OABP, GCN20, and White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance.
This protein is thought to form ATP-sensitive potassium channels in cardiac, skeletal, and vascular and non-vascular smooth muscle. Protein structure suggests a role as the drug-binding channel modulating subunit of the extra-pancreatic ATP-sensitive potassium channels. Mutations in this gene are associated with cardiomyopathy dilated type 1O. Alternative splicing results in multiple transcript variants.

Genomic Context:
Chromosome 12; Location 12p12.1

ABCC6/MRP6 transporter
In Pseudoxanthoma Elasticum (PXE) ABCC6 has been found to alter the properties of sulfated glycosaminoglycans.
Researchers believe the presence of altered GAGS in PXE results from an inherited genetic defect in the ABC transporter called ABCC6/MRP6. PXE is a hereditary connective tissue in which proteoglycans have altered properties. PXE is a disease which shares commonalities to interstitial cystitis because in PXE chemical alterations to the sulfated glycosaminoglycans heparan sulfate and chondriotin sulfate occur. In one study the sulfated glycosaminoglycans in the urine of PXE



ABCB1 or MDR1 P-glycoprotein
ABCB1 is involved in other biological processes for which lipid transport is the main function. It is found to mediate the secretion of the steroid aldosterone by the adrenals and its inhibition blocked the migration of dendritic immune cells, possibly related to the outward transport of the lipid platelet activating factor (PAF). It has also been reported that ABCB1 mediates the transport of cortisol and dexametasone, but not of progesterone in ABCB1 transected cells. MDR1 can also transport cholesterol, short-chain and long chain analogues of phosphatidycholaine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), sphinogomyelin (SM), and glucoasylerimide (Glc)Cer.

The human ABCB (MDR/TAP family) is responsible for multi-drug-resistance, (MDR) against a variety of structurally unrelated drugs.

The problem of autoimmune disease patients of having an abnormally high resistance to medications may possibly be explained by abnormalities in ABCB1.
This is a eukaryotic ABC protein. Although most eukaryotic ABC transporters are effluxers, some are not directly involved in transporting substrates. In the cystic fibrosis transmembrane regulator (CFTR) and in the sulfonylurea receptor, ATP hydrolysis is associated with the regulation of opening and closing of ion channels carried by the ABC protein itself or other proteins.
Human ABC transporters are involved in several diseases that arise from polymorphisms in ABC genes and rarely due to complete loss of function by ABC proteins. Such diseases include Mendealian diseases and complex genetic disorders such as cystic fibrosis, adrenoleukodaystrophy, Pseudoxanthoma elasticum, and more.
(Source: Wikipedia, ABC transporters article)
XMRV Viral homologues to human
Proteins.
ABCC9/ EAW96452.1 ATP binding cassette, sub family C (CFTR/MRP, member 9, isoform.
This protein is thought to form ATP sensitive potassium channels in cardiac, skeletal and vascular and non-vascular smooth muscle.
Homologous proteins
[LE* D*IFP*RF MP*+]
ATP2C1 EAW79217.1 ATPase, Ca+ transporting, type 2C, member 1, isoform CRA_a[Homo
This magnesium dependent enzyme catalyzes the hydrolysis of ATP coupled with the transport of calcium, XMRV ENV.

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Here now are some studies and articles which lay out how there is something very unique going on with ATP and what it binds to in interstitial cystitis. One very interesting tidbit worth knowing is that abnormal breakdown of tryptophan to kynurenine; a process that happens in my disease, yours and fibromyalgia has been linked to extracellular ATP and its affects on dendrite development. Yes, I'm not going to be wasting your time- I'm sharing information which seems to be getting so fruitful, I am struggling to get through all of it.

Oh, BTW, here's that article about Antiproliferative Factor, p53 and IC: "P53 regulates two ATP-generating pathways; p53 is gene responsible for Antiproliferative Factor (APF) in interstitial cystitis
Differential Utilization of two ATP-regulating pathways is regulated by p53
by Wissam Assaily and Samuel Benchimol, Department of Biology, York University, Toronto, Ontario, Canada.
http://www.sciencedirect.com/science/article/pii/S15356108060019166

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its ME Jeff said:

Very interesting! I am XMRV+ and suffer with M.E. My wife suffers from I.C. She has not been tested for XMRV.

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Allergies and Sensitivities
Celiac Disease
Chronic Fatigue Syndrome
Chronic Prostatitis
Endometriosis
Fibromyalgia
Irritable Bowel Syndrome
Lupus
Pelvic Floor Dysfunction
Pudendal Neuralgia
Sjogrens Syndrome
Vulvodynia

Individuals with allergies, migraine headaches, endometriosis, irritable bowel syndrome, asthma, or sensitive skin may have a greater chance of developing IC. And, some studies have reported that IC patients are as much as 100 times more likely than the general population to have irritable bowel syndrome.
Vulvodynia, a syndrome marked by various painful vulvovaginal symptoms, is the fourth most common IC-related condition. It is thought that a common defect in the bladder and the vaginal tissues may contribute to both conditions.
Individuals already suffering from IC may also have a greater chance of developing fibromyalgia or chronic fatigue syndrome.
IC patients have been shown to be 30 times more likely than the general population to have systemic lupus erythematosus.
More recent research has revealed that IC may also be connected with certain other chronic conditions, such as panic attacks and pelvic floor dysfunction.

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warriormom said:

Very interesting. My daughter had the IC symptoms and diagnosis before CFS/ME onset. Is the Ruta Graveolens available at GNC?

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Hip said:

Ruta graveolens is a bit of an obscure herb, so you you'll probably have to buy it online.

I suggest buying Ruta graveolens as bulk powder, as it is much cheaper than way:

Ruta graveolens powder (US)
Ruta graveolens powder (UK)

You can also buy Ruta graveolens in tinctures, but it is best to go for bulk sizes (like or a liter or more), as smaller size tinctures work out expensive, given that you need to take 2 ml (= 0.07 fluid ounces) or more each day.

Ruta graveolens tincture (US)
Ruta graveolens tincture (UK)

Avoid any homeopathic formulations of Ruta graveolens, as there is no Ruta graveolens whatsoever within such formulations you might as well drink pure water (which what homeopathic formulations are).

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