TRPM7 ion channels are required for sustained phosphoinositide 3-kinase signaling in lymphocytes
Jaya Sahni1, Andrew M Scharenberg
1Department of Pediatrics, University of Washington and Seattle Children's Hospital Research Institute, Seattle, WA 98101, USA.
Abstract:
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.
Insights
Lymphocytes lacking TRPM7 channels cannot grow without sufficient extracellular Mg2+. TRPM7 is essential for sustained phosphoinositide 3-kinase signaling, regulating lymphocyte proliferation.
Area of Science:
- Cell Biology
- Ion Channel Physiology
- Molecular Signaling
Background:
- Lymphocytes require specific ion concentrations for proliferation.
- TRPM7 (transient receptor potential cation channel, subfamily M, member 7) is a dual ion channel and protein kinase.
- TRPM7-deficient lymphocytes show impaired proliferation in standard media but recover with Mg2+ supplementation.
Purpose of the Study:
- To elucidate the molecular mechanisms behind the unique proliferation phenotype of TRPM7-deficient lymphocytes.
- To investigate the role of TRPM7 in regulating lymphocyte growth and proliferation signaling pathways.
Main Methods:
- Analysis of TRPM7-deficient lymphocytes transitioning between Mg2+-supplemented and regular media.
- Assessment of cell growth rates and proliferation.
- Investigation of phosphoinositide 3-kinase (PI3K) signaling pathways downstream of TRPM7.
Main Results:
- TRPM7-deficient cells downregulate growth and arrest proliferation when Mg2+ is removed.
- This growth arrest correlates with PI3K signaling deactivation.
- Expressing constitutively active PI3K rescues growth and proliferation in regular media.
Conclusions:
- TRPM7 channels are crucial for maintaining sustained PI3K-dependent growth signaling in lymphocytes.
- TRPM7 acts as a central regulator of lymphocyte growth and proliferation, alongside PI3K.
- TRPM7's function is vital for lymphocyte homeostasis, particularly under varying extracellular Mg2+ conditions.
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