Inactivation of TRPM2 channels by extracellular divalent copper

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Abstract

© 2014 Yu et al. Cu 2+ is an essential metal ion that plays a critical role in the regulation of a number of ion channels and receptors in addition to acting as a cofactor in a variety of enzymes. Here, we showed that human melastatin transient receptor potential 2 (hTRPM2) channel is sensitive to inhibition by extracellular Cu 2+ . Cu 2 + at concentrations as low as 3 μM inhibited the hTRPM2 channel completely and irreversibly upon washing or using Cu 2+ chelators, suggesting channel inactivation. The Cu 2+ -induced inactivation was similar when the channels conducted inward or outward currents, indicating the permeating ions had little effect on Cu 2+ -induced inactivation. Furthermore, Cu2+ had no effect on singe channel conductance. Alanine substitution by site-directed mutagenesis of His995 in the pore-forming region strongly attenuated Cu 2+ -induced channel inactivation, and mutation of several other pore residues to alanine altered the kinetics of channel inactivation by Cu 2+ . In addition, while introduction of the P1018L mutation is known to result in channel inactivation, exposure to Cu 2+ accelerated the inactivation of this mutant channel. In contrast with the hTRPM2, the mouse TRPM2 (mTRPM2) channel, which contains glutamine at the position equivalent to His995, was insensitive to Cu 2+ . Replacement of His995 with glutamine in the hTRPM2 conferred loss of Cu 2+ -induced channel inactivation. Taken together, these results suggest that Cu 2+ inactivates the hTRPM2 channel by interacting with the outer pore region. Our results also indicate that the amino acid residue difference in this region gives rise to species-dependent effect by Cu 2+ on the human and mouse TRPM2 channels.

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Yu, W., Jiang, L. H., Zheng, Y., Hu, X., Luo, J., & Yang, W. (2014). Inactivation of TRPM2 channels by extracellular divalent copper. PLoS ONE, 9(11). https://doi.org/10.1371/journal.pone.0112071

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