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Inhibition of the Magnesium-Sensitive TRPM7-like Channel in Cardiac Myocytes by Nonhydrolysable GTP Analogs: Involvement of Phosphoinositide Metabolism

Background/Aims: A magnesium-inhibited, transient receptor potential melastatin 7 (TRPM7)-like channel is expressed in cardiac cell membranes. The role and regulation of this channel by intracellular nucleotides and membrane components remain unclear. Methods: We used the whole-cell voltage-clamp technique in pig isolated ventricular myocytes to investigate the effect of non-hydrolysable guanine nucleotides. Results: The TRPM7-like current, induced by intracellular dialysis with low [Mg2+], remained stable when the intracellular solution contained GTP. Substituting GTP by GTP-γ-S or Gp-pNp, but not GDP-β-S, induced a run-down of the current. Under dialysis with GTP-γ-S, inhibiting phospholipase C by edelfosine or intracellularly adding exogenous phosphatidylinositol-4,5-bisphosphate (PIP2) decreased run-down, whereas extracellularly applying carbachol and phenylephrine accelerated it. Pretreatment of cells with pertussis toxin did not prevent the run-down induced by GTP-γ-S. Conclusion: Guanine nucleotides can modulate cardiac TRPM7-like channels via a mechanism linked to G proteins and to PIP2 metabolism.