Basolateral Mg2+ Extrusion via CNNM4 Mediates Transcellular Mg2+ Transport across Epithelia: A Mouse Model

Daisuke Yamazaki, Yosuke Funato, Jiro Miura, Sunao Sato, Satoru Toyosawa, Kazuharu Furutani, Yoshihisa Kurachi, Yoshihiro Omori, Takahisa Furukawa, Tetsuya Tsuda, Susumu Kuwabata, Shin Mizukami, Kazuya Kikuchi, Hiroaki Miki

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Transcellular Mg2+ transport across epithelia, involving both apical entry and basolateral extrusion, is essential for magnesium homeostasis, but molecules involved in basolateral extrusion have not yet been identified. Here, we show that CNNM4 is the basolaterally located Mg2+ extrusion molecule. CNNM4 is strongly expressed in intestinal epithelia and localizes to their basolateral membrane. CNNM4-knockout mice showed hypomagnesemia due to the intestinal malabsorption of magnesium, suggesting its role in Mg2+ extrusion to the inner parts of body. Imaging analyses revealed that CNNM4 can extrude Mg2+ by exchanging intracellular Mg2+ with extracellular Na+. Furthermore, CNNM4 mutations cause Jalili syndrome, characterized by recessive amelogenesis imperfecta with cone-rod dystrophy. CNNM4-knockout mice showed defective amelogenesis, and CNNM4 again localizes to the basolateral membrane of ameloblasts, the enamel-forming epithelial cells. Missense point mutations associated with the disease abolish the Mg2+ extrusion activity. These results demonstrate the crucial importance of Mg2+ extrusion by CNNM4 in organismal and topical regulation of magnesium.

Original languageEnglish (US)
Article numbere1003983
JournalPLoS Genetics
Volume9
Issue number12
DOIs
StatePublished - Dec 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Yamazaki, D., Funato, Y., Miura, J., Sato, S., Toyosawa, S., Furutani, K., Kurachi, Y., Omori, Y., Furukawa, T., Tsuda, T., Kuwabata, S., Mizukami, S., Kikuchi, K., & Miki, H. (2013). Basolateral Mg2+ Extrusion via CNNM4 Mediates Transcellular Mg2+ Transport across Epithelia: A Mouse Model. PLoS Genetics, 9(12), [e1003983]. https://doi.org/10.1371/journal.pgen.1003983