In this issue of Pflügers Archiv European Journal of Physiology, Liebe et al. describe the properties of bTRPV3 (bovine transient receptor potential vanilloid type 3) channels expressed in model systems such as HEK-293 cells or Xenopus oocytes. By using a combination of different methods such as pH- and voltage-sensitive microelectrodes or patch-clamp recordings, they demonstrate that this channel is highly permeable for NH4+. This cation is produced in large amounts in the forestomach during the degradation of proteins and non-protein nitrogen compounds by microbes living in symbiosis with the ruminant . With a pKa value of 9.2, NH4+ is the overwhelming form in the chemical equilibrium between NH3 (ammonium) and NH4+ (ammonia) at the slightly acidic pH values within the ruminal content. The expression of this channel in the bovine ruminal epithelium makes it a good candidate as the (or one of the) transport proteins for NH4+. Ammonia is rapidly absorbed from the forestomach, converted to urea in the liver and recycled into the forestomach as substrate for microbial protein synthesis or excreted via the urine. Probably, TRPV3 is also the molecular basis for the long-known divalent-sensitive cation conductance found in the forestomach epithelium .
Transport of NH4+/NH3 has up to now thought to be mediated by simple non-ionic diffusion of the gas NH3 or by renal rhesus-associated glycoproteins, members of the SLC42 solute transporter family able to transport both NH4+ and NH3 . Furthermore, many K+ channels and transporters accept NH4+ instead of K+ due to the similar hydrated radius (1.45 Å) of both ions . This property has been elegantly used in transport physiological studies to measure e.g. activity of Na+-K+-2 Cl−-transporters (NKCC) via bumetanide-sensitive acidification in the presence of extracellular NH4+ [5, 7].
The present study of Liebe et al. now adds a new player, bTRPV3, to the list of transporters involved in ammonia transport. When regarding the biophysical properties of this unselective cation channel, bTRPV3 shows a remarkably high permeability for N-methyl-D-glucamine+ (NMDG+), which is often used as ‘impermeant’ ion during cation substitution experiments. Despite the large molecular size of NMDG+, which is estimated to cover a volume of 6 Å × 6 Å × 12.5 Å , fitting of shifts in zero-current potential during ion replacement experiments to the Goldman-Huxley-Katz equation revealed a permeability for NMDG+ of about 45 % in comparison with that for Na+. Due to these properties and its permeability even for divalent cations such as Ca2+, demonstrated by the same research group , it is well possible that beside ammonia absorption, also other absorptive functions of the ruminal epithelium may involve TRPV3.
The study of Liebe et al. has relevance for several fields. Production of climate gases such as N2O from cattle urine (starting from urea produced during the hepatic metabolism of NH4+ absorbed by the forestomach) is a severe environmental problem . So, basic knowledge about the physiological mechanisms of ruminal NH4+ absorption delivering the substrate for urea production is urgently needed. A further outlook of the present study is the question whether TRPV3 or similar channels may be involved in the absorption of NH4+ from the large intestine such as caecum or colon, where also significant amounts of ammonium are absorbed. Healthy individuals protect their central nervous system from NH3/NH4+ by hepatic conversion into urea; any hepatic failure can therefore lead to encephalopathy. As many members of the superfamily of TRP channels can be pharmacologically activated or inhibited by different drugs or natural compounds (see ), these channels might be promising candidates for new therapeutic strategies.
Caner T, Abdulnour-Nakhoul S, Brown K, Islam MT, Hamm LL, Nakhoul NL (2015) Mechanisms of ammonia and ammonium transport by rhesus-associated glycoproteins. Am J Physiol Cell Physiol 309:C747–C758. https://doi.org/10.1152/ajpcell.00085.2015
Chadwick DR, Cardenas LM, Dhanoa MS, Donovan N, Misselbrook TJ, Williams JR, Thorman RE, KL MG, Watson CJ, Bell M, Anthony SG, Reese RM (2018) The contribution of cattle urine and dung to nitrous oxide emissions: quantification of country specific emission factors and implications for national inventories. Sci Total Environ 635:607–617. https://doi.org/10.1016/j.scitotenv.2018.04.152
Concise Guide to Pharmacology (2020) http://www.guidetopharmacology.org/ (visited ApriL, 22, 2020)
Harkat M, Peverini L, Cerdan AH, Dunning K, Beudez J, Martz A, Calimet N, Specht A, Cecchini M, Chataigneau T, Grutter T (2017) On the permeation of large organic cations through the pore of ATP-gated P2X receptors. Proc Natl Acad Sci USA 114:E3786–E3795. https://doi.org/10.1073/pnas.1701379114
Heitmann D, Warth R, Bleich M, Henger A, Nitschke R, Greger R (2000) Regulation of Na+2Cl-K+ cotransporter in isolated rat colon crypts. Pflügers Arch Eur J Physiol 439:378–384. https://doi.org/10.1007/s004249900156
Knepper MA, Packer R, Good DW (1989) Ammonium transport in the kidney. Physiol Rev 69:179–249
Reynolds A, Parris A, Evans LA, Lindqvist S, Sharp P, Lewis M, Tighe R, Williams MR (2007) Dynamic and differential regulation of NKCC1 by calcium and cAMP in the native human colonic epithelium. J Physiol 582:507–524. https://doi.org/10.1113/jphysiol.2007.129718
Reynolds CK, Kristensen NB (2008) Nitrogen recycling through the gut and the nitrogen economy of ruminants: an asynchronous symbiosis. J Anim Sci 86(Suppl. 14):E293–E305. https://doi.org/10.2527/jas.2007-0475
Schrapers KT, Sponder G, Liebe F, Liebe H, Stumpff F (2018) The bovine TRPV3 as a pathway for the uptake of Na+, Ca2+, and NH4+. PLoS One 13:e0193519. https://doi.org/10.1371/journal.pone.0193519
Schultheiss G, Martens H (1999) Ca-sensitive Na transport in sheep omasum. Am J Physiol 276:G1331–G1344. https://doi.org/10.1152/ajpgi.1999.276.6.G1331
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Diener, M. New ways for an old cation. Pflugers Arch - Eur J Physiol 472, 669–670 (2020). https://doi.org/10.1007/s00424-020-02394-1