Wei WL, Sun HS, Olah ME, Sun X, Czerwinska E, Czerwinski W, Mori Y, Orser BA, Xiong ZG, Jackson MF, Tymianski M, MacDonald JF. (2007) Proc Natl Acad Sci. 104(41):16323-8.

Abstract

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 Galphaq-linked G protein-coupled receptors linked to phospholipase C beta1-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.

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