Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) potentiates cardiac contractility via activation of the ryanodine receptor

Chad D. Touchberry, Ian K. Bales, Jessica K. Stone, Travis J. Rohrberg, Nikhil K. Parelkar, Tien Nguyen, Oscar Fuentes, Xia Liu, Cheng Kui Qu, Jon J. Andresen, Héctor H. Valdivia, Marco Brotto, Michael J. Wacker

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is the most recently identified phosphoinositide, and its functions have yet to be fully elucidated. Recently, members of our muscle group have shown that PI(3,5)P2 plays an important role in skeletal muscle function by altering Ca2+ homeostasis. Therefore, we hypothesized that PI(3,5)P2 may also modulate cardiac muscle contractility by altering intracellular Ca2+ ([Ca 2+]i) in cardiac myocytes. We first confirmed that PI(3,5)P2 was present and increased by insulin treatment of cardiomyocytes via immunohistochemistry. To examine the acute effects of PI(3,5)P2 treatment, electrically paced left ventricular muscle strips were incubated with PI(3,5)P2. Treatment with PI(3,5)P2 increased the magnitude of isometric force, the rate of force development, and the area associated with the contractile waveforms. These enhanced contractile responses were also observed in MIP/Mtmr14 -/- mouse hearts, which we found to have elevated levels of PI(3,5)P2. In cardiac myocytes loaded with fura-2, PI(3,5)P2 produced a robust elevation in [Ca2+]i. The PI(3,5)P2-induced elevation of [Ca2+]i was not present in conditions free of extracellular Ca2+ and was completely blocked by ryanodine. We investigated whether the phosphoinositide acted directly with the Ca 2+ release channels of the sarcoplasmic reticulum (ryanodine receptors; RyR2). PI(3,5)P2 increased [3H]ryanodine binding and increased the open probability (Po) of single RyR2 channels reconstituted in lipid bilayers. This strongly suggests that the phosphoinositide binds directly to the RyR2 channel. Thus, we provide inaugural evidence that PI(3,5)P2 is a powerful activator of sarcoplasmic reticulum Ca2+ release and thereby modulates cardiac contractility.

Original languageEnglish
Pages (from-to)40312-40321
Number of pages10
JournalJournal of Biological Chemistry
Issue number51
StatePublished - Dec 17 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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