Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7.
TRPM7 is a polypeptide with intrinsic ion channel and protein kinase domains whose targeted deletion causes cells to experience growth arrest within 24 hr and eventually die. Here, we show that while TRPM7's kinase domain is not essential for activation of its channel, a functional coupling exists such that structural alterations of the kinase domain alter the sensitivity of channel activation to Mg(2+). Investigation of the relationship between Mg(2+) and the cell biological role of TRPM7 revealed that TRPM7-deficient cells become Mg(2+) deficient, that both the viability and proliferation of TRPM7-deficient cells are rescued by supplementation of extracellular Mg(2+), and that the capacity of heterologously expressed TRPM7 mutants to complement TRPM7 deficiency correlates with their sensitivity to Mg(2+). Overall, our results indicate that TRPM7 has a central role in Mg(2+) homeostasis as a Mg(2+) uptake pathway regulated through a functional coupling between its channel and kinase domains.
Schmitz
Carsten
C
Department of Pediatrics, University of Washington and Children's Hospital and Regional Medical Center, Seattle, WA 98195, USA.
Perraud
Anne-Laure
AL
Johnson
Catherine O
CO
Inabe
Kazunori
K
Smith
Megan K
MK
Penner
Reinhold
R
Kurosaki
Tomohiro
T
Fleig
Andrea
A
Scharenberg
Andrew M
AM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology / Q000502:physiology*; D010770:Phosphotransferases / Q000378:metabolism; D017354:Point Mutation; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017384:Sequence Deletion; D014162:Transfection
D007473:Ion Channels; D000255:Adenosine Triphosphate; D010770:Phosphotransferases; D011494:Protein Kinases; D008274:Magnesium