June 2023 - Martin Schepelmann

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Mag. pharm. Dr. Martin Schepelmann

MedUni Wien RESEARCHER OF THE MONTH June 2023

Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells

The Calcium-Sensing Receptor (CaSR) that can be found in blood vessels but there its function had remained rather unclear. We developed and characterized a mouse model where the CaSR had been removed from the blood vessels via genetic manipulation. We discovered that the CaSR in blood vessels protects vascular muscle cells from calcification. Furthermore, we found that the CaSR in the blood vessels directly contributes to controlling blood calcium levels by influencing production of specific mineral ion metabolism related hormones like calcitriol, FGF23, and PTH. These findings constitute a paradigm shift in our understanding of physiological mineral ion control in the body and can contribute to explain the pathophysiological mineral ion disturbances in observed in renal failure patients.

Selected Literature

1. Schepelmann M, Ranieri M, Lopez-Fernandez I, Webberley TS, Brennan SC, Yarova PL, Graca J, Hanif UK, Muller C, Manhardt T, Salzmann M, Quasnichka H, Price SA, Ward DT, Gilbert T, Matchkov VV, Fenton RA, Herberger A, Hwong J, Santa Maria C, Tu CL, Kallay E, Valenti G, Chang W, Riccardi D. Impaired Mineral Ion Metabolism in a Mouse Model of Targeted Calcium-Sensing Receptor (CaSR) Deletion from Vascular Smooth Muscle Cells. J Am Soc Nephrol. 2022. https://doi.org/10.1681/ASN.2021040585

2. Brown EM. Role of the calcium-sensing receptor in extracellular calcium homeostasis. Best Pract Res Clin Endocrinol Metab. 2013;27(3):333-43. https://doi.org/10.1016/j.beem.2013.02.006

3. Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018;15(1):33-51. https://doi.org/10.1038/s41574-018-0115-0

4. Schepelmann M, Molcan L, Uhrova H, Zeman M, Ellinger I. The presence and localization of melatonin receptors in the rat aorta. Cell Mol Neurobiol. 2011;31(8):1257-65. https://doi.org/10.1007/s10571-011-9727-9

5. Schepelmann M, Yarova PL, Lopez-Fernandez I, Davies TS, Brennan SC, Edwards PJ, Aggarwal A, Graca J, Rietdorf K, Matchkov V, Fenton RA, Chang W, Krssak M, Stewart A, Broadley KJ, Ward DT, Price SA, Edwards DH, Kemp PJ, Riccardi D. The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure. Am J Physiol Cell Physiol. 2016;310(3):C193-204. https://doi.org/10.1152/ajpcell.00248.2015

6. Yarova PL, Huang P, Schepelmann MW, Bruce R, Ecker R, Nica R, Telezhkin V, Traini D, Gomes Dos Reis L, Kidd EJ, Ford WR, Broadley KJ, Kariuki BM, Corrigan CJ, Ward JPT, Kemp PJ, Riccardi D. Characterization of Negative Allosteric Modulators of the Calcium-Sensing Receptor for Repurposing as a Treatment of Asthma. J Pharmacol Exp Ther. 2021;376(1):51-63. https://doi.org/10.1124/jpet.120.000281

7. Yarova PL, Stewart AL, Sathish V, Britt RD, Jr., Thompson MA, AP PL, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang W, Bin Khayat ME, Ward DT, Corrigan CJ, JP TW, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Sci Transl Med. 2015;7(284):284ra60. https://doi.org/10.1126/scitranslmed.aaa0282

8. Schepelmann M, Kupper N, Sladczyk M, Mansfield B, Manhardt T, Piatek K, Iamartino L, Riccardi D, Kariuki BM, Bassetto M, Kallay E. Stereo-Specific Modulation of the Extracellular Calcium-Sensing Receptor in Colon Cancer Cells. Int J Mol Sci. 2021;22(18). https://doi.org/10.3390/ijms221810124

9. Iamartino L, Elajnaf T, Gall K, David J, Manhardt T, Heffeter P, Grusch M, Derdak S, Baumgartner-Parzer S, Schepelmann M, Kallay E. Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor. Biochim Biophys Acta Mol Cell Res. 2020;1867(12):118836. https://doi.org/10.1016/j.bbamcr.2020.118836

10.  Elajnaf T, Iamartino L, Mesteri I, Muller C, Bassetto M, Manhardt T, Baumgartner-Parzer S, Kallay E, Schepelmann M. Nutritional and Pharmacological Targeting of the Calcium-Sensing Receptor Influences Chemically Induced Colitis in Mice. Nutrients. 2019;11(12). https://doi.org/10.3390/nu11123072

11.  Iamartino L, Elajnaf T, Kallay E, Schepelmann M. Calcium-sensing receptor in colorectal inflammation and cancer: Current insights and future perspectives. World J Gastroenterol. 2018;24(36):4119-31. https://doi.org/10.3748/wjg.v24.i36.4119

12.  Schepelmann M, Kupper N, Gushchina V, Mesteri I, Manhardt T, Moritsch S, Muller C, Piatek K, Salzmann M, Vlasaty A, Eferl R, Kallay E. AOM/DSS Induced Colitis-Associated Colorectal Cancer in 14-Month-Old Female Balb/C and C57/Bl6 Mice-A Pilot Study. Int J Mol Sci. 2022;23(9). https://doi.org/10.3390/ijms23095278