TRPM7 residue S1269 mediates cAMP dependence of Ca2+ influx

PLoS One. 2019 Jan 7;14(1):e0209563. doi: 10.1371/journal.pone.0209563. eCollection 2019.

Abstract

The nonspecific divalent cation channel TRPM7 (transient receptor potential-melastatin-like 7) is involved in many Ca2+ and Mg2+-dependent cellular processes, including survival, proliferation and migration. TRPM7 expression predicts metastasis and recurrence in breast cancer and several other cancers. In cultured cells, it can induce an invasive phenotype by promoting Ca2+-mediated epithelial-mesenchymal transition. We previously showed that in neuroblastoma cells that overexpress TRPM7 moderately, stimulation with Ca2+-mobilizing agonists leads to a characteristic sustained influx of Ca2+. Here we report that sustained influx through TRPM7 is abruptly abrogated by elevating intracellular levels of cyclic adenosine monophosphate (cAMP). Using pharmacological inhibitors and overexpression studies we show that this blockage is mediated by the cAMP effector Protein Kinase A (PKA). Mutational analysis demonstrates that the Serine residue S1269, which is present proximal to the coiled-coil domain within the protein c-terminus, is responsible for sensitivity to cAMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Calcium Signaling / drug effects
  • Cell Line, Tumor
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Isoquinolines / pharmacology
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Sulfonamides / pharmacology
  • TRPM Cation Channels / metabolism*

Substances

  • Isoquinolines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • TRPM Cation Channels
  • Cyclic AMP
  • Trpm7 protein, mouse
  • Cyclic AMP-Dependent Protein Kinases
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
  • Calcium

Grant support

Funded by KWF kankerbestrijding grant NKI 2010-4626. To dr K. Jalink.