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Received May 3, 2004
Revised June 7, 2004
Accepted after revision July 16, 2004
1 University of Leuven
2 Boston University
* To whom correspondence should be addressed. E-mail: kanigula.mubagwa{at}med.kuleuven.ac.be.
Cardiac tissue expresses several TRP proteins as well as a Mg2+-inhibited, non-selective cation current (IMIC) that bears many characteristics of TRP channel currents. We used the whole-cell voltage clamp technique in pig and rat ventricular myocytes to characterize the permeation, blockage properties and regulation of the cardiac IMIC channels in order to compare them with TRP channels, in particular with Mg2+-sensitive TRPM6 and TRPM7. We show that removing extracellular divalent cations unmasks large inward and outward monovalent currents, that can be inhibited by intracellular Mg2+. Inward currents are suppressed upon replacing extracellular Na+ by NMDG+. Divalent cations block monovalent IMIC and, at 10-20 mM, carry measurable currents. Their efficacy sequence in decreasing outward IMIC (Ni2+ ? Mg2+ > Ca2+ > Ba2+) and in inducing inward IMIC (Ni2+ >> Mg2+ ? Ca2+ ? Ba2+), and their permeabilities calculated from reversal potentials are similar to those of TRPM6 and TRPM7 channels. The trivalent cations Gd3+ and Dy3+ also block IMIC in a voltage-dependent manner (d = 0.4-0.5). In addition they inhibit the inward current carried by divalent cations. IMIC is regulated by pH. Decreasing or increasing extracellular pH decreased and increased IMIC, respectively (pH0.5 = 6.9, nHill = 0.98). Qualitatively similar results were obtained on IMIC in rat basophilic lymphocytes. These effects in cardiac myocytes were absent in the presence of high intracellular buffering by 40 mM HEPES. Our results suggest that IMIC in cardiac cells is due to TRPM channels, most probably to TRPM6 or TRPM7 channels or to their heteromultimeres.
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