ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

Am J Physiol Cell Physiol. 2006 Oct;291(4):C627-35. doi: 10.1152/ajpcell.00074.2006. Epub 2006 May 17.


The Mg(2+)-inhibited cation (MIC) current (I(MIC)) in cardiac myocytes biophysically resembles currents of heterologously expressed transient receptor potential (TRP) channels, particularly TRPM6 and TRPM7, known to be important in Mg(2+) homeostasis. To understand the regulation of MIC channels in cardiac cells, we used the whole cell voltage-clamp technique to investigate the role of intracellular ATP in pig, rat, and guinea pig isolated ventricular myocytes. I(MIC), studied in the presence or absence of extracellular divalent cations, was sustained for >or=50 min after patch rupture in ATP-dialyzed cells, whereas in ATP-depleted cells I(MIC) exhibited complete rundown. Equimolar substitution of internal ATP by its nonhydrolyzable analog adenosine 5'-(beta,gamma-imido)triphosphate failed to prevent rundown. In ATP-depleted cells, inhibition of lipid phosphatases by fluoride + vanadate + pyrophosphate prevented I(MIC) rundown. In contrast, under similar conditions neither the inhibition of protein phosphatases 1, 2A, 2B or of protein tyrosine phosphatase nor the activation of protein kinase A (forskolin, 20 microM) or protein kinase C (phorbol myristate acetate, 100 nM) could prevent rundown. In ATP-loaded cells, depletion of phosphatidylinositol 4,5-bisphosphate (PIP(2)) by prevention of its resynthesis (10 microM wortmannin or 15 microM phenylarsine oxide) induced rundown of I(MIC). Finally, loading ATP-depleted cells with exogenous PIP(2) (10 microM) prevented rundown. These results suggest that PIP(2), likely generated by ATP-utilizing lipid kinases, is necessary for maintaining cardiac MIC channel activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology
  • Adenosine Triphosphate / physiology*
  • Animals
  • Cations, Divalent / pharmacology
  • Electric Conductivity
  • Guinea Pigs
  • Heart Ventricles
  • Hydrolysis
  • Magnesium / pharmacology*
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Phosphatidylinositol 4,5-Diphosphate / antagonists & inhibitors
  • Phosphatidylinositol 4,5-Diphosphate / physiology*
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Swine
  • TRPM Cation Channels / antagonists & inhibitors*
  • TRPM Cation Channels / drug effects
  • TRPM Cation Channels / metabolism*
  • TRPM Cation Channels / physiology
  • Time Factors


  • Cations, Divalent
  • Phosphatidylinositol 4,5-Diphosphate
  • Protein Kinase Inhibitors
  • TRPM Cation Channels
  • Adenosine Triphosphate
  • Trpm7 protein, rat
  • Phosphoprotein Phosphatases
  • Phosphoric Monoester Hydrolases
  • Magnesium