TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations.
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.
Wei
Wen-Li
WL
Department of Physiology, University of Toronto, 1 King's College Circle, Toronto, ON, Canada M5S 1A8.
Sun
Hong-Shuo
HS
Olah
Michelle E
ME
Sun
Xiujun
X
Czerwinska
Elzbieta
E
Czerwinski
Waldemar
W
Mori
Yasuo
Y
Orser
Beverley A
BA
Xiong
Zhi-Gang
ZG
Jackson
Michael F
MF
Tymianski
Michael
M
MacDonald
John F
JF
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002413:Cations, Divalent / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D002413:Cations, Divalent; D011994:Recombinant Proteins; D050053:TRPM Cation Channels; C421903:Trpm7 protein, mouse