Article: Charge screening by internal pH and polyvalent cations as a mechanism for activation, inhibition, and rundown of TRPM7/MIC channels.
The Journal of general physiology
2005 Volume 126, Issue 5, Page(s) 499–514
Abstract: ... patches. We propose that MIC (TRPM7) channels are regulated by a charge screening mechanism and ... The nature of divalent inhibition and the mechanism of channel activation in an intact cell remain unknown ... The Mg2+-inhibited cation (MIC) current, believed to represent activity of TRPM7 channels, is found ...
| Abstract | The Mg2+-inhibited cation (MIC) current, believed to represent activity of TRPM7 channels, is found in lymphocytes and mast cells, cardiac and smooth muscle, and several other eukaryotic cell types. MIC current is activated during whole-cell dialysis with divalent-free internal solutions. Millimolar concentrations of intracellular Mg2+ (or other divalent metal cations) inhibit the channels in a voltage-independent manner. The nature of divalent inhibition and the mechanism of channel activation in an intact cell remain unknown. We show that the polyamines (spermine, spermidine, and putrescine) inhibit the MIC current, also in a voltage-independent manner, with a potency that parallels the number of charges. Neomycin and poly-lysine also potently inhibited MIC current in the absence of Mg2+. These same positively charged ions inhibited IRK1 current in parallel with MIC current, suggesting that they probably act by screening the head group phosphates on PIP2 and other membrane phospholipids. In agreement with this hypothesis, internal protons also inhibited MIC current. By contrast, tetramethylammonium, tetraethylammonium, and hexamethonium produced voltage-dependent block but no inhibition. We show that inhibition by internal polyvalent cations can be relieved by alkalinizing the cytosol using externally applied ammonium or by increasing pH in inside-out patches. Furthermore, in perforated-patch and cell-attached recordings, when intracellular Mg2+ is not depleted, endogenous MIC or recombinant TRPM7 currents are activated by cytosolic alkalinization and inhibited by acidification; and they can be reactivated by PIP2 following rundown in inside-out patches. We propose that MIC (TRPM7) channels are regulated by a charge screening mechanism and may function as sensors of intracellular pH. |
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| MeSH term(s) | Animals ; CHO Cells/drug effects ; CHO Cells/physiology ; Cations/metabolism ; Cations/pharmacology ; Cricetinae ; Cytosol/drug effects ; Cytosol/physiology ; Hydrogen-Ion Concentration ; Magnesium/antagonists & inhibitors ; Magnesium/pharmacology ; Magnesium/physiology ; Membrane Potentials/drug effects ; Membrane Potentials/physiology ; Patch-Clamp Techniques ; Phosphatidylinositol 4,5-Diphosphate/pharmacology ; Phosphatidylinositol 4,5-Diphosphate/physiology ; Phospholipids/physiology ; Polyamines/pharmacology ; Potassium Channels, Inwardly Rectifying/physiology ; Recombinant Fusion Proteins ; Second Messenger Systems/physiology ; TRPM Cation Channels/drug effects ; TRPM Cation Channels/genetics ; TRPM Cation Channels/physiology ; Transfection | |||||
| Chemical Substances | Cations ; Phosphatidylinositol 4,5-Diphosphate ; Phospholipids ; Polyamines ; Potassium Channels, Inwardly Rectifying ; Recombinant Fusion Proteins ; TRPM Cation Channels ; Trpm7 protein, mouse (EC 2.7.1.-) ; Magnesium (I38ZP9992A) | |||||
| Language | English | |||||
| Publishing date | 2005-11 | |||||
| Publishing country | United States | |||||
| Document type | Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 3118-5 | |||||
| ISSN | 1540-7748 ; 0022-1295 | |||||
| ISSN (online) | 1540-7748 | |||||
| ISSN | 0022-1295 | |||||
| DOI | 10.1085/jgp.200509324 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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