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Omeprazole enhances the colonic expression of the Mg2+ transporter TRPM6

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, used by millions of patients suffering from gastric acid-related complaints. Although PPIs have an excellent safety profile, an increasing number of case reports describe patients with severe hypomagnesemia due to long-term PPI use. As there is no evidence of a renal Mg2+ leak, PPI-induced hypomagnesemia is hypothesized to result from intestinal malabsorption of Mg2+. The aim of this study was to investigate the effect of PPIs on Mg2+ homeostasis in an in vivo mouse model. To this end, C57BL/6J mice were treated with omeprazole, under normal and low dietary Mg2+ availability. Omeprazole did not induce changes in serum Mg2+ levels (1.48 ± 0.05 and 1.54 ± 0.05 mmol/L in omeprazole-treated and control mice, respectively), urinary Mg2+ excretion (35 ± 3 μmol/24 h and 30 ± 4 μmol/24 h in omeprazole-treated and control mice, respectively), or fecal Mg2+ excretion (84 ± 4 μmol/24 h and 76 ± 4 μmol/24 h in omeprazole-treated and control mice, respectively) under any of the tested experimental conditions. However, omeprazole treatment did increase the mRNA expression level of the transient receptor potential melastatin 6 (TRPM6), the predominant intestinal Mg2+ channel, in the colon (167 ± 15 and 100 ± 7 % in omeprazole-treated and control mice, respectively, P < 0.05). In addition, the expression of the colonic H+,K+-ATPase (cHK-α), a homolog of the gastric H+,K+-ATPase that is the primary target of omeprazole, was also significantly increased (354 ± 43 and 100 ± 24 % in omeprazole-treated and control mice, respectively, P < 0.05). The expression levels of other magnesiotropic genes remained unchanged. Based on these findings, we hypothesize that omeprazole inhibits cHK-α activity, resulting in reduced extrusion of protons into the large intestine. Since TRPM6-mediated Mg2+ absorption is stimulated by extracellular protons, this would diminish the rate of intestinal Mg2+ absorption. The increase of TRPM6 expression in the colon may compensate for the reduced TRPM6 currents, thereby normalizing intestinal Mg2+ absorption during omeprazole treatment in C57BL/6J mice, explaining unchanged serum, urine, and fecal Mg2+ levels.

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Acknowledgments

We kindly thank Henk Arnts and Jeroen Mooren for technical assistance and Dr. Joost Drenth for critical reading of the manuscript. This study was supported by the Netherlands Organization for Scientific Research [TOP ZonMw 91208026, NWO-ALW 818.02.001], a EURYI award from the European Science Foundation and the Dutch Kidney Foundation [C08.2252] and EURenOmics funding from the European Union seventh Framework Programme (FP7/2007-2013, agreement n° 305608). Mark Hess was supported by a grant of the Institute for Genetic and Metabolic Disease (IGMD) of the Radboud University Nijmegen Medical Centre.

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Authors and Affiliations

  1. Department of Physiology, Nijmegen Centre for Molecular Life Science, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    A. L. L. Lameris, M. W. Hess, I. van Kruijsbergen, J. G. J. Hoenderop & R. J. M. Bindels

  2. Department of Physiology (286), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    R. J. M. Bindels

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  1. A. L. L. Lameris
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  3. I. van Kruijsbergen
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  4. J. G. J. Hoenderop
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  5. R. J. M. Bindels
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Correspondence to R. J. M. Bindels.

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Lameris, A.L.L., Hess, M.W., van Kruijsbergen, I. et al. Omeprazole enhances the colonic expression of the Mg2+ transporter TRPM6. Pflugers Arch - Eur J Physiol 465, 1613–1620 (2013). https://doi.org/10.1007/s00424-013-1306-0

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  • DOI: https://doi.org/10.1007/s00424-013-1306-0

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