Article: TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations.
Proceedings of the National Academy of Sciences of the United States of America
2007 Volume 104, Issue 41, Page(s) 16323–16328
Abstract: ... by which hippocampal neurons "detect" reductions in extracellular divalents and provide a means by which TRPM7 ... the initial condition of the Ca(2+) paradox. In CA1 hippocampal neurons, lowering extracellular divalents ... expression in hippocampal neurons strongly depressed the inward currents evoked by lowering extracellular ...
| Abstract | Exposure to low Ca(2+) and/or Mg(2+) is tolerated by cardiac myocytes, astrocytes, and neurons, but restoration to normal divalent cation levels paradoxically causes Ca(2+) overload and cell death. This phenomenon has been called the "Ca(2+) paradox" of ischemia-reperfusion. The mechanism by which a decrease in extracellular Ca(2+) and Mg(2+) is "detected" and triggers subsequent cell death is unknown. Transient periods of brain ischemia are characterized by substantial decreases in extracellular Ca(2+) and Mg(2+) that mimic the initial condition of the Ca(2+) 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 Mg(2+), (iv) are enhanced by intracellular phosphatidylinositol 4,5-bisphosphate (PIP(2)), and (v) can be inhibited by Galphaq-linked G protein-coupled receptors linked to phospholipase C beta1-induced hydrolysis of PIP(2). 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. |
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| MeSH term(s) | Animals ; Brain Ischemia/metabolism ; Brain Ischemia/pathology ; Cations, Divalent/metabolism ; Cell Death/physiology ; Cells, Cultured ; Hippocampus/cytology ; Hippocampus/metabolism ; Humans ; Mice ; Neurons/metabolism ; RNA Interference ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Reperfusion Injury/metabolism ; Reperfusion Injury/pathology ; TRPM Cation Channels/antagonists & inhibitors ; TRPM Cation Channels/genetics ; TRPM Cation Channels/metabolism ; Transfection |
| Chemical Substances | Cations, Divalent ; Recombinant Proteins ; TRPM Cation Channels ; Trpm7 protein, mouse (EC 2.7.1.-) |
| Language | English |
| Publishing date | 2007-10-03 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 209104-5 |
| ISSN | 1091-6490 ; 0027-8424 |
| ISSN (online) | 1091-6490 |
| ISSN | 0027-8424 |
| DOI | 10.1073/pnas.0701149104 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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