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RNase L in Chronic Fatigue Syndrome (ME/CFS): A Channelopathy? An Overview from Patrick Englebienne

Englebienne, P., Herst, C. V., De Smet, K., D’Haese, A. and K. De Meirleir. 2001.  Interactions Between RNase L Ankyrin-like Domain and ABC Transporters as a Possible Origin for Pain, Ion Transport, CNS and Immune Disorders of Chronic Fatigue Immune Dysfunction Syndrome. Journal of Chronic Fatigue Syndrome 8 (3/4): 83-102

(This was published prior to CFS ABA.  Much of the information is found in CFS ABA.  Some, however, is new).

The authors note that CFS patients exhibit many symptoms (including pain) that are characteristic of ion channel transport dysfunction. (Ion channels occur in all membranes.  They facilitate the transfer of ions and other substances into and out of the organelles in cells and of cells themselves.)

The potential for ion channel disruption in CFS patients was noted when it was determined that the RNase L’s inhibitor (RLI), belonged to the ABC superfamily of ion channel transporters.  RLI inactivates RNase L by binding to the ‘ankyrin domain’ section of the enzyme.

The breakup of the ankyrin domain during the RNase L fragmentation seen in CFS patients suggested that these ankyrin fragments may be able to interact with and disrupt ion channel functioning.  Ankyrins are proteins that (among other things) link the cells cytoskeleton to membrane proteins. They control the shape and elasticity of the cell membrane.

In order to determine which ABC transporters RLI was most similar to the authors made a ‘sequence search’ of a genetic database at the National Center for Biotechnology Information (NCBI) . Because ABC transporters typically interact with ‘ankyrin domains’ the authors sought to determine if RLI and other ABC transporters shared similar ankyrin interacting motifs   If they did then it would mean that the ankyrin motifs released during RNase L fragmentation could potentially interact with ABC transporters found in the cell.

Eleven ABC transporters with substantial homologies to RLI were found. They shared with RLI an amino acid motif that allowed them to interact with ankyrins in the cells cytoplasm.  Interestingly enough, given the high rate of chemical sensitivities found in people with CFS, several ‘multidrug resistance transporters’ involved in removing toxic materials from cells were found.

These channels are also involved in the transport of choline and monamine transporters.  (Both may be disrupted in CFS).  By disrupting glandular functioning in the epithelial tissues (skin, intestines, bronchii, etc.), one channel involved in chloride (Na) transport could cause night sweats and sarcoidosis (a topic of recent interest).  Disruption of the SUR I channel could cause muscular weakness through losses of intracellular potassium.

Another ABC transporter f(ABC3 )plays an important role in the engulfment of  apoptotic cells by macrophages.(Might a dysfunctional engulfment process lead to elastase deposition in the cell? One wonders if this transporter is tied to antigen processing as well?)

The ABC7 protein transports heme from the mitochondria to the cytosol.  ABC8 regulates macrophage cholesterol and is involved in tryptophan uptake. (Some reports suggest trytophan levels are increased in CFS.)  ABC8 dysfunction has been tied to several neurological diseases. TAP I is important in antigen processing and presentation by MHC I molecules.

The authors suggest fragmentation of the RNase L enzymes releases ankyrin fragments that have the potential to interfere with the function of several ABC transporters.  They note that ABC transporter dysfunction could account for the following symptoms found in CFS patients: nightsweats, sarcoidosis, chemical hypersensitivities, macrophage dysfunction, immune deficiency, altered monoamine transport, increased pain sensitivity, Th2 dominance, CNS abnormalities, vision problems, potassium losses in muscles, transient hypoglycemia, depression (!).

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