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The TRPM7 kinase limits receptor-induced calcium release by regulating heterotrimeric G-proteins.

Abstract
The melastatin-related transient receptor potential member 7 (TRPM7) is a unique fusion protein with both ion channel function and enzymatic α-kinase activity. TRPM7 is essential for cellular systemic magnesium homeostasis and early embryogenesis; it promotes calcium transport during global brain ischemia and emerges as a key player in cancer growth. TRPM7 channels are negatively regulated through G-protein-coupled receptor-stimulation, either by reducing cellular cyclic adenosine monophosphate (cAMP) or depleting phosphatidylinositol bisphosphate (PIP2) levels in the plasma membrane. We here identify that heterologous overexpression of human TRPM7-K1648R mutant will lead to disruption of protease or purinergic receptor-induced calcium release. The disruption occurs at the level of Gq, which requires intact TRPM7 kinase phosphorylation activity for orderly downstream signal transduction to activate phospholipase (PLC)β and cause calcium release. We propose that this mechanism may support limiting GPCR-mediated calcium signaling in times of insufficient cellular ATP supply.
AuthorsSayuri Suzuki, Annette Lis, Carsten Schmitz, Reinhold Penner, Andrea Fleig
JournalCellular and molecular life sciences : CMLS (Cell Mol Life Sci) Vol. 75 Issue 16 Pg. 3069-3078 (08 2018) ISSN: 1420-9071 [Electronic] Switzerland
PMID29500477 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Receptors, G-Protein-Coupled
  • TRPM Cation Channels
  • Cyclic AMP
  • Protein Serine-Threonine Kinases
  • TRPM7 protein, human
  • Thrombin
  • Heterotrimeric GTP-Binding Proteins
  • Calcium
Topics
  • Calcium (metabolism)
  • Cyclic AMP (metabolism)
  • HEK293 Cells
  • Heterotrimeric GTP-Binding Proteins (metabolism)
  • Humans
  • Intracellular Space (drug effects, metabolism)
  • Mutation, Missense
  • Phosphorylation
  • Protein Serine-Threonine Kinases (genetics, metabolism)
  • Receptors, G-Protein-Coupled (metabolism)
  • TRPM Cation Channels (genetics, metabolism)
  • Thrombin (pharmacology)

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