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Abstract: FR-PO308

The Influence of MUC1 on Mg2+ Handling

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Lam, Tracey, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Al-bataineh, Mohammad M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Marciszyn, Allison L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Ye, Lorena, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Singh, Amrit, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Poland, Paul A., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Kinlough, Carol L., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Emlet, David R., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Ray, Evan C., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Hughey, Rebecca P., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Numerous genomic studies find an association between the common MUC1 polymorphism rs4072037 (minor allele frequency 21-47%) and circulating Mg2+ levels. This polymorphism in exon 1 of MUC1 alters mRNA splicing, elongating the N-terminus of mature MUC1. It is referred to as the long-signal peptide variant (LSP), as compared to the short-signal peptide variant (SSP). Although human genome association studies have found an association between the LSP variant and hypomagnesemia, no studies have demonstrated an effect of MUC1 on Mg2+ balance.

MUC1 is known to enhance cell surface localization of Ca2+-selective TRP channels (TRPV5 and TRPV6). MUC1 is co-expressed with the Mg2+-selective channel, TRPM6 in the kidney’s distal convoluted tubule (DCT). TRPM6 is a key mediator of renal Mg2+ handling. Reduced TRPM6 cell surface expression in response to blockage of the epidermal growth factor receptor (EGFR), leads to urinary Mg2+ wasting and hypomagnesemia.

We hypothesized that MUC1 influences TRPM6 cell surface expression, contributing to renal tubular reabsorption of Mg2+, and that LSP-MUC1 does this less effectively than SSP-MUC1.

Methods

We examined plasma Mg2+ levels in Muc1-/- mice and studied MUC1 and TRPM6 expression in polarized MDCK cells and in human kidney tissue samples.

Results

We find that Muc1-/- mice are hypomagnesemic. In polarized MDCK cells in culture, MUC1 co-immunoprecipitates with TRPM6 and its binding partner, TRPM7. MUC1 enhances cell surface expression of TRPM6 and TRPM7. Although the majority of MUC1 is expressed at the apical surface of polarized epithelial cells, a small fraction is expressed basolaterally, where EGFR is located. Both in MDCK cells and in human kidney tissue, that fraction of MUC1 is reduced in the LSP variant as compared to the SSP variant. EGFR is more heavily phosphorylated in response to basolateral EGF in MDCK cells expressing SSP-MUC1 compared with LSP-MUC1, suggesting that SSP-MUC1 enhances activation of the EGFR receptor, promoting activation of TRPM6.

Conclusion

These studies provide a mechanistic explanation for the influence of MUC1 upon Mg2+ homeostasis. On-going studies are exploring the specific importance of kidney tubule MUC1 for TRPM6 activity and Mg2+ balance and EGFR-dependence of differences in TRPM6 cell surface expression associated with the LSP vs SSP MUC1 variants.

Funding

  • NIDDK Support