TRPM7 ion channels are required for sustained phosphoinositide 3-kinase signaling in lymphocytes.
Lymphocytes lacking the TRPM7 (transient receptor potential cation channel, subfamily M, member 7) dual function ion channel/protein kinase exhibit a unique phenotype: they are unable to proliferate in regular media, but proliferate normally in media supplemented with 10-15 mM extracellular Mg(2+). Here, we have analyzed the molecular mechanisms underlying this phenotype. We find that upon transition from proliferation-supporting Mg(2+)-supplemented media to regular media, TRPM7-deficient cells rapidly downregulate their rate of growth, resulting in a secondary arrest in proliferation. The downregulated growth rate of transitioning cells is associated with a deactivation of signaling downstream from phosphoinositide 3-kinase, and expression of constitutively active p110 phosphoinositide 3-kinase is sufficient to support growth and proliferation of TRPM7-deficient cells in regular media. Together, these observations indicate that TRPM7 channels are required for sustained phosphoinositide 3-kinase-dependent growth signaling and therefore, that TRPM7 is positioned alongside phosphoinositide 3-kinases as a central regulator of lymphocyte growth and proliferation.
Sahni
Jaya
J
Department of Pediatrics, University of Washington and Seattle Children's Hospital Research Institute, Seattle, WA 98101, USA.
Scharenberg
Andrew M
AM
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002645:Chickens; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D008274:Magnesium; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D050053:TRPM Cation Channels / Q000502:physiology*
D050053:TRPM Cation Channels; D019869:Phosphatidylinositol 3-Kinases; D008274:Magnesium