TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations

Exposure to low Ca²⁺ and/or Mg²⁺ is tolerated by cardiac myocytes, astrocytes, and neurons, but restoration to normal divalent cation levels paradoxically causes Ca²⁺ overload and cell death. This phenomenon has been called the "Ca²⁺ paradox" of ischemia-reperfusion. The mechanism by which...

Full description

Saved in:
Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-10, Vol.104 (41), p.16323-16328
Main Authors: Wei, Wen-Li, Sun, Hong-Shuo, Olah, Michelle E, Sun, Xiujun, Czerwinska, Elzbieta, Czerwinski, Waldemar, Mori, Yasuo, Orser, Beverley A, Xiong, Zhi-Gang, Jackson, Michael F, Tymianski, Michael, MacDonald, John F
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biological Sciences
Brain diseases
Brain Ischemia - metabolism
Brain Ischemia - pathology
Calcium
Cations, Divalent - metabolism
Cell death
Cell Death - physiology
Cells, Cultured
Cultured cells
Divalent cations
Electric current
Electric potential
HEK293 cells
Hippocampus - cytology
Hippocampus - metabolism
Humans
Ions
Magnesium
Mice
Neurons
Neurons - metabolism
Paradoxes
Pipettes
Receptors
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Reperfusion Injury - metabolism
Reperfusion Injury - pathology
RNA Interference
Transfection
TRPM Cation Channels - antagonists & inhibitors
TRPM Cation Channels - genetics
TRPM Cation Channels - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Exposure to low Ca²⁺ and/or Mg²⁺ is tolerated by cardiac myocytes, astrocytes, and neurons, but restoration to normal divalent cation levels paradoxically causes Ca²⁺ overload and cell death. This phenomenon has been called the "Ca²⁺ paradox" of ischemia-reperfusion. The mechanism by which a decrease in extracellular Ca²⁺ and Mg²⁺ is "detected" and triggers subsequent cell death is unknown. Transient periods of brain ischemia are characterized by substantial decreases in extracellular Ca²⁺ and Mg²⁺ that mimic the initial condition of the Ca²⁺ paradox. In CA1 hippocampal neurons, lowering extracellular divalents stimulates a nonselective cation current. We show that this current resembles TRPM7 currents in several ways. Both (i) respond to transient decreases in extracellular divalents with inward currents and cell excitation, (ii) demonstrate outward rectification that depends on the presence of extracellular divalents, (iii) are inhibited by physiological concentrations of intracellular Mg²⁺, (iv) are enhanced by intracellular phosphatidylinositol 4,5-bisphosphate (PIP₂), and (v) can be inhibited by Gαq-linked G protein-coupled receptors linked to phospholipase C β1-induced hydrolysis of PIP₂. Furthermore, suppression of TRPM7 expression in hippocampal neurons strongly depressed the inward currents evoked by lowering extracellular divalents. Finally, we show that activation of TRPM7 channels by lowering divalents significantly contributes to cell death. Together, the results demonstrate that TRPM7 contributes to the mechanism by which hippocampal neurons "detect" reductions in extracellular divalents and provide a means by which TRPM7 contributes to neuronal death during transient brain ischemia.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0701149104