TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations

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 ischemiareperfusion. 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 G␣q-linked G protein-coupled receptors linked to phospholipase C ␤1-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.calcium paradox ͉ divalent cation sensing ͉ siRNA ͉ ischemia

Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca 2+ regulation of neuronal excitability

“…In addition, CALHM1 has a considerable Ca 2+ permeability. These properties distinguish CALHM1 from these other channels and suggest that it could be important in neuronal activities for which mechanisms are still unclear, for example fast activity-dependent modulation of neurotransmission (23) and the "Ca 2+ paradox" associated with neuronal death during excitotoxic stimulation (10,34). The Ca 2+ paradox describes a phenomenon observed in heart and neurons (including hippocampus) (10,35,36) 2+ ] o is restored to normal levels, the latter often constituting a toxic insult (10,(37)(38)(39).…”

“…NALCN, a Na + leak channel (33) with minimal Ca 2+ permeability, is activated in hippocampal pyramidal cells indirectly by low [Ca 2+ ] o by a G-protein-coupled receptor (11). TRPM7 can also be activated in hippocampal neurons under conditions in which divalent cation concentrations fall, although normal intracellular Mg 2+ levels are expected to minimize such activation (34). In contrast, CALHM1 is regulated in cortical neurons by [Ca 2+ ] o directly, in a process that is coupled to an intrinsic voltage-dependent gating mechanism.…”

Molecular identification of ancient and modern mammalian magnesium transporters

“…It is appealing to speculate that the expanded poly(Q) tract alters huntingtin binding with its associated proteins, so that endocytic vesicle trafficking of HIP14 is abnormal, leading to aberrant release or accumulation of divalent cations into these organelles. This notion has gained some support from studies using various cell and animal models (35,86,91,153,173). Given the pleiotropic nature of huntingtin functions, it is unlikely that altered cation transport is the sole cause of Huntington's disease, but a clearer picture of HIP14 physiology should increase our understanding of the disease progression.…”

TRPM7 in cerebral ischemia and potential target for drug development in stroke

“…In N1E-115 neuroblastoma cells, HA-tagged TRPM7 antibodies were localized in membrane ruffl es [45] . Similarly, protein expression of TRPM7 is also shown in cell bodies and processes of hippocampal neurons with immunostaining [4,47,48] . In superior cervical ganglion neurons, TRPM7 is exclusively localized within cholinergic vesicles [49] .…”