Molecular determinants of sensitivity and conductivity of human TRPM7 to Mg2+ and Ca2+

Channels
Tomohiro Numata, Yasunobu Okada

Abstract

It is known that extracellular Mg(2+) and Ca(2+) can permeate TRPM7 and at the same time block the permeation by monovalent cations. In the present study, we examined the molecular basis for the conductivity and sensitivity of human TRPM7 to these divalent cations. Extracellular acidification to pH 4.0 markedly reduced the blocking effects of Mg(2+) and Ca(2+) on the Cs(+) currents, decreasing their binding affinities: their IC(50) values increased 510- and 447-fold, respectively. We examined the effects of neutralizing each of four negatively charged amino acid residues, Glu-1047, Glu-1052, Asp-1054 and Asp-1059, within the putative pore-forming region of human TRPM7. Mutating Glu-1047 to alanine (E1047A) resulted in non-functional channels, whereas mutating any of the other residues resulted in functionally expressed channels. Cs(+) currents through D1054A and E1052A were less sensitive to block by divalent cations; the IC(50) values were increased 5.5- and 3.9-fold, respectively, for Mg(2+) and 10.5- and 6.7-fold, respectively, for Ca(2+). D1059A also had a significant reduction, though less marked compared to the reductions seen for D1054A and E1052A, in sensitivity to Mg(2+) (1.7-fold) and Ca(2+) (3.9-fold). The D1054A mut...Continue Reading

Citations

Jul 10, 2009·American Journal of Physiology. Cell Physiology·Sulochana DeviVijayasaradhi Setaluri
May 18, 2016·The Journal of General Physiology·Wolfgang NörenbergMichael Schaefer
Jul 31, 2014·European Journal of Cell Biology·Daan VisserKees Jalink
Sep 16, 2016·Scientific Reports·Chad JansenAndrea Fleig
Jun 12, 2019·Channels·Ana Elena López-RomeroTamara Rosenbaum
Sep 26, 2009·Molecular Pharmacology·Zuzana SaidakRomuald Mentaverri
May 22, 2021·Communications Biology·Tomohiro NumataYasunobu Okada

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