Human CNNM2 is not a Mg2+ transporter per se

  • Gerhard Sponder
  • Lucia Mastrototaro
  • Katharina Kurth
  • Lucia Merolle
  • Zheng Zhang
  • Nasrin Abdulhanan
  • Alina Smorodchenko
  • Katharina Wolf
  • Andrea Fleig
  • Reinhold Penner
  • Stefano Iotti
  • Jörg R. Aschenbach
  • Jürgen Vormann
  • Martin KolisekEmail author
Ion channels, receptors and transporters


CNNM2 is associated with the regulation of serum Mg concentration, and when mutated, with severe familial hypomagnesemia. The function and cellular localization of CNNM2 and its isomorphs (Iso) remain controversial. The objective of this work was to examine the following: (1) the transcription-responsiveness of CNNM2 to Mg starvation, (2) the cellular localization of Iso1 and Iso2, (3) the ability of Iso1 and Iso2 to transport Mg2+, and (4) the complex-forming ability and spectra of potential interactors of Iso1 and Iso2. The five main findings are as follows. (1) Mg-starvation induces CNNM2 overexpression that is markedly higher in JVM-13 cells (lymphoblasts) compared with Jurkat cells (T-lymphocytes). (2) Iso1 and Iso2 localize throughout various subcellular compartments in transgenic HEK293 cells overexpressing Iso1 or Iso2. (3) Iso1 and Iso2 do not transport Mg2+ in an electrogenic or electroneutral mode in transgenic HEK293 cells overexpressing Iso1 or Iso2. (4) Both Iso1 and Iso2 form complexes of a higher molecular order. (5) The spectrum of potential interactors of Iso1 is ten times smaller than that of Iso2. We conclude that sensitivity of CNNM2 expression to extracellular Mg2+ depletion depends on cell type. Iso1 and Iso2 exhibit a dispersed pattern of cellular distribution; thus, they are not exclusively integral to the cytoplasmic membrane. Iso1 and Iso2 are not Mg2+ transporters per se. Both isomorphs form protein complexes, and divergent spectra of potential interactors of Iso1 and Iso2 indicate that each isomorph has a distinctive function. CNNM2 is therefore the first ever identified Mg2+ homeostatic factor without being a Mg2+ transporter per se.


Magnesium Homeostasis Patch clamp Mag-fura 2 Protein interactions Mitochondria 



Our gratitude is due to Martin Marak (Freie Universität Berlin) for competent technical support of the project, to Dr. Svenja Plöger-Meissner (Freie Universität Berlin) for help with the confocal microscopy, to Dr. Mandana Rezwan (Dualsystems Biotech AG) for cooperation with the construction of the cell lines, and to Dr. Katrin Rutschmann (Dualsystems Biotech AG) for cooperation with the SU-YTHa. Our thanks are also extended to Dr. Theresa Jones for linguistic corrections.

This work was supported by research grants from the German Research Foundation (DFG), KO-3586/3-1 and KO-3586/3-2 to MK and by research grant from Protina Pharmazeutische GmbH to JV and MK.


MK designed the study; GS, LMa, KK, LMe, ZZ, NA, AS, KW, AF, RP, and MK performed the experiments and analyzed the data; GS, AF, RP, SI, JRA, and JV contributed to the study design; MK wrote the manuscript. All authors read, edited, and approved the manuscript.

Compliance with ethical standards

Competing interests

JV is a scientific consultant of Protina Pharmazeutische GmbH. Other authors have no conflict of interests to disclose.

Supplementary material

424_2016_1816_MOESM1_ESM.doc (469 kb)
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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Gerhard Sponder
    • 1
  • Lucia Mastrototaro
    • 1
  • Katharina Kurth
    • 1
    • 5
  • Lucia Merolle
    • 2
    • 6
  • Zheng Zhang
    • 3
  • Nasrin Abdulhanan
    • 1
  • Alina Smorodchenko
    • 1
    • 7
  • Katharina Wolf
    • 1
  • Andrea Fleig
    • 3
  • Reinhold Penner
    • 3
  • Stefano Iotti
    • 2
  • Jörg R. Aschenbach
    • 1
  • Jürgen Vormann
    • 4
  • Martin Kolisek
    • 1
    Email author
  1. 1.Institute of Veterinary-PhysiologyFree University of BerlinBerlinGermany
  2. 2.Department of Pharmacy and BiotechnologyUniversity of BolognaBolognaItaly
  3. 3.The Queen’s Medical Center, Center for Biomedical ResearchHonoluluUSA
  4. 4.Institute for Prevention and Nutrition (IPEV)MunichGermany
  5. 5.Landesuntersuchungsanstalt SachsenDresdenGermany
  6. 6.Elettra—Sincrotrone Trieste S.C.p.A.BasovizzaItaly
  7. 7.Institute of Vegetative AnatomyCharité - Universitätsmedizin BerlinBerlinGermany

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