uncategorized alternative medicine

Fluoride Channels

This site has addressed the role of CIC family of Cl-/H+ antiporters in lysosomal function. It has been brought to my attention that Drs Chris Miller and Randy Stockbridge discovered a homolog in bacteria. ShunHui Ji was first author of a review [1] that will be used as a starting point.

This topic is being pursued because many readers are concerned by the affect of municipal water fluorination on human health. Wikipedia authors state that 3 liters of municipal water may contain about 2.4 mg of fluoride while just 240 ml of brewed black tea contains 0.88 mg fluoride. As a reminder, there are 1000mL in a liter.

From Ji et al 2014 [1] At pH 3.4 half of HF is in this “protonated” lipid permeable form and the other half is in the form of H+ and F. Once HF enters the bacterial cell F- and H+ predominate. This is what Li and coauthors are proposing for acidic natural environments. We can presume the same is true for cells of our oral cavities after consuming acidic beverages or when oral growth of bacteria have decreased the pH.
  1. the and the “Fluc” family of F-specific ion channels, also found in eukaryotes. These F exporters are part of the multidrug resistance transporters that protect all organisms from natural organic xenobiotics and man-made drugs. F/H+ antiporters, like multidrug resistance pumps, use energy sources (proton gradients or ATP hydrolysis) to drive thermodynamically uphill efflux of unwanted substrates. [1] After some literature digging, the Flux analog, called Flex in plants and animals. [2]
  2. an exclusively prokaryotic clade of F/H+ antiporters of the CLC anion-transporter super family

Fluc, Fex in select eukaryotes

These fluoride channels work against a concentration gradient by using the inside negative membrane potential. .For a bacterial cell with a −100-mV potential, the equilibrium level of cytoplasmic F would be ∼50-fold lower than the extracellular concentration, i.e., <1 µM (far below inhibitory levels. We have to remember that bacteria have an outside positive membrane potential by virtue of their electron transport chain that is analogous to our mitochondria. Another group established the importance of the fungal, plant, and select animal analog Fex. [2] The group failed to find a convincing analog in land mammals. This could be because of hard to decipher slicing schemes and limited homology. [2] Other strategies may exist for removal of excess chloride.

Top Alignment of protein sequences from six eukaryotic and two bacterial fluoride channels.Transmembrane regions were predicted using TMHMM and TMpred servers. Conserved residues for all eukaryotic FEX proteins are highlighted with asterisks. Amino acid numbering corresponds to the protein sequence of Fex1p from S. cerevisiae. The residues highlighted in green are present within both pores of Fluc [2]. Bottom left
The helices from both domains that form functional and vestigial pores. [2] Bottom right The outside positive membrane potential in eukaryotic cells is driven by the Na/K pump. It is this electrical gradient that moves F- out of ukaryote cells.

Note that A queenslanacia is a sea sponge found in the Great Barrier Reef. This animal is exposed to flouride in the ocean in ways that land mammals simply are not. [2] What are the ramifications of human oral exposure to fluoride via black tea, floridated tooth paste, and so on if our microflora is equipped to deal with fluoride when our mucosa is not?

References

  1. Ji C, Stockbridge RB, Miller C. Bacterial fluoride resistance, Fluc channels, and the weak acid accumulation effect. J Gen Physiol. 2014 Sep;144(3):257-61 PMC free article
  2. Berbasova T, Nallur S, Sells T, Smith KD, Gordon PB, Tausta SL, Strobel SA. Fluoride export (FEX) proteins from fungi, plants and animals are ‘single barreled’ channels containing one functional and one vestigial ion pore. PLoS One. 2017 May 4;12(5):e0177096. PMC free article
  3. Last NB, Stockbridge RB, Wilson AE, Shane T, Kolmakova-Partensky L, Koide A, Koide S, Miller C. A CLC-type F/H+ antiporter in ion-swapped conformations. Nat Struct Mol Biol. 2018 Jul;25(7):601-606. PMC free article
  4. Fahlke C. Ion permeation and selectivity in ClC-type chloride channels. Am J Physiol Renal Physiol. 2001 May;280(5):F748-57. free article
  5. Lim HH, Stockbridge RB, Miller C. Fluoride-dependent interruption of the transport cycle of a CLC Cl-/H+ antiporter. Nat Chem Biol. 2013 Nov;9(11):721-5.PMC free article
  6. Ran S, Sun N, Liu Y, Zhang W, Li Y, Wei L, Wang J, Liu B. Fluoride resistance capacity in mammalian cells involves complex global gene expression changes. FEBS Open Bio. 2017 Jun 5;7(7):968-980. PMC free article

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