The Journal of General Physiology
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Published online Oct 31 2005. doi:10.1085/jgp.200509324
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 126, Number 5, 499-514
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ARTICLE

 Charge Screening by Internal pH and Polyvalent Cations as a Mechanism for Activation, Inhibition, and Rundown of TRPM7/MIC Channels

J. Ashot Kozak1, Masayuki Matsushita2, Angus C. Nairn3, and Michael D. Cahalan1

1 Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA 92697
2 First Department of Physiology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
3 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508

Correspondence to Michael D. Cahalan: mcahalan{at}uci.edu

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.

Abbreviations used in this paper: CHO, Chinese hamster ovary; MBP, myelin basic protein; MIC, Mg2+-inhibited cation.


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