title: Human CNNM2 is not a Mg(2+) transporter per se.
abstract: 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 Mg(2+), 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 Mg(2+) 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 Mg(2+) 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 Mg(2+) 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 Mg(2+) homeostatic factor without being a Mg(2+) transporter per se.
authors.affiliation: Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Sponder
authors.affiliation: Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mastrototaro
authors.affiliation: Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany.|Landesuntersuchungsanstalt Sachsen, Jägerstraße 8/10, Dresden, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kurth
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Massarenti 9, Bologna, Italy.|Elettra-Sincrotrone Trieste S.C.p.A., Strada Statale 14 AREA Science Park, Basovizza, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Merolle
authors.affiliation: The Queen's Medical Center, Center for Biomedical Research, 1356 Lusitana Street, UH Tower 8, Honolulu, HI, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany.
authors.forename: Nasrin
authors.initials: N
authors.lastname: Abdulhanan
authors.affiliation: Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany.|Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Philippstrasse 12, Berlin, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Smorodchenko
authors.affiliation: Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wolf
authors.affiliation: The Queen's Medical Center, Center for Biomedical Research, 1356 Lusitana Street, UH Tower 8, Honolulu, HI, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
authors.affiliation: The Queen's Medical Center, Center for Biomedical Research, 1356 Lusitana Street, UH Tower 8, Honolulu, HI, USA.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Penner
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Massarenti 9, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Iotti
authors.affiliation: Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany.
authors.forename: Jörg R
authors.initials: JR
authors.lastname: Aschenbach
authors.affiliation: Institute for Prevention and Nutrition (IPEV), Adalperostrasse 37, Munich, Ismaning, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Vormann
authors.affiliation: Institute of Veterinary-Physiology, Free University of Berlin, Oertzenweg 19b, 14163, Berlin, Germany. martink@zedat.fu-berlin.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Kolisek
mesh_terms: D001692:Biological Transport / Q000502:physiology; D027682:Cation Transport Proteins; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D008274:Magnesium / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: C558175:CNNM2 protein, human; D027682:Cation Transport Proteins; D016213:Cyclins; D026901:Membrane Transport Proteins; D008274:Magnesium
keywords: Homeostasis; Mag-fura 2; Magnesium; Mitochondria; Patch clamp; Protein interactions