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Cell Mol Life Sci. 2018 Aug;75(16):3069-3078. doi: 10.1007/s00018-018-2786-z. Epub 2018 Mar 2.

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

Author information

1
Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., Honolulu, HI, 96813, USA.
2
John A. Burns School of Medicine, University of Hawaii Cancer Center, University of Hawaii, 651 Ilalo St, Honolulu, HI, 96813, USA.
3
Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), School of Medicine, Saarland University, 66421, Homburg/Saar, Germany.
4
Integrated Department of Immunology, National Jewish Health, University of Colorado Denver, Denver, CO, 80206, USA.
5
Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., Honolulu, HI, 96813, USA. afleig@hawaii.edu.
6
John A. Burns School of Medicine, University of Hawaii Cancer Center, University of Hawaii, 651 Ilalo St, Honolulu, HI, 96813, USA. afleig@hawaii.edu.

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.

KEYWORDS:

Heterotrimeric G-protein; TRPM7; α-Kinase

PMID:
29500477
PMCID:
PMC6033657
DOI:
10.1007/s00018-018-2786-z
[Indexed for MEDLINE]
Free PMC Article

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