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Influence of glycoprotein MUC1 on trafficking of the Ca2+-selective ion channels, TRPV5 and TRPV6, and on in vivo calcium homeostasis

MM. Al-Bataineh, CL. Kinlough, A. Marciszyn, T. Lam, L. Ye, K. Kidd, JC. Maggiore, PA. Poland, S. Kmoch, A. Bleyer, DJ. Bain, N. Montalbetti, TR. Kleyman, RP. Hughey, EC. Ray

. 2023 ; 299 (3) : 102925. [pub] 20230120

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, N.I.H., Extramural

Perzistentní odkaz   https://www.medvik.cz/link/bmc23003959

Grantová podpora
K08 DK110332 NIDDK NIH HHS - United States
T32 DK061296 NIDDK NIH HHS - United States
K01 DK109038 NIDDK NIH HHS - United States
R03 DK131093 NIDDK NIH HHS - United States
R01 DK038470 NIDDK NIH HHS - United States
P30 DK079307 NIDDK NIH HHS - United States

Polymorphism of the gene encoding mucin 1 (MUC1) is associated with skeletal and dental phenotypes in human genomic studies. Animals lacking MUC1 exhibit mild reduction in bone density. These phenotypes could be a consequence of modulation of bodily Ca homeostasis by MUC1, as suggested by the previous observation that MUC1 enhances cell surface expression of the Ca2+-selective channel, TRPV5, in cultured unpolarized cells. Using biotinylation of cell surface proteins, we asked whether MUC1 influences endocytosis of TRPV5 and another Ca2+-selective TRP channel, TRPV6, in cultured polarized epithelial cells. Our results indicate that MUC1 reduces endocytosis of both channels, enhancing cell surface expression. Further, we found that mice lacking MUC1 lose apical localization of TRPV5 and TRPV6 in the renal tubular and duodenal epithelium. Females, but not males, lacking MUC1 exhibit reduced blood Ca2+. However, mice lacking MUC1 exhibited no differences in basal urinary Ca excretion or Ca retention in response to PTH receptor signaling, suggesting compensation by transport mechanisms independent of TRPV5 and TRPV6. Finally, humans with autosomal dominant tubulointerstitial kidney disease due to frame-shift mutation of MUC1 (ADTKD-MUC1) exhibit reduced plasma Ca concentrations compared to control individuals with mutations in the gene encoding uromodulin (ADTKD-UMOD), consistent with MUC1 haploinsufficiency causing reduced bodily Ca2+. In summary, our results provide further insight into the role of MUC1 in Ca2+-selective TRP channel endocytosis and the overall effects on Ca concentrations.

Citace poskytuje Crossref.org

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