Phosphatidylinositol-4,5-Bisphosphate Binding to Amphiphysin-II Modulates T-Tubule Remodeling: Implications for Heart Failure

Junlan Zhou, Neha Singh, Chloe Monnier, William Marszalec, Li Gao, Jing Jin, Michael Frisk, William E. Louch, Suresh Verma, Prasanna Krishnamurthy, Elsa Nico, Maaz Mulla, Gary L Aistrup, Raj Kishore, J. Andrew Wasserstrom*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


BIN1 (amphyphysin-II) is a structural protein involved in T-tubule (TT) formation and phosphatidylinositol-4,5-bisphosphate (PIP2) is responsible for localization of BIN1 to sarcolemma. The goal of this study was to determine if PIP2-mediated targeting of BIN1 to sarcolemma is compromised during the development of heart failure (HF) and is responsible for TT remodeling. Immunohistochemistry showed co-localization of BIN1, Cav1.2, PIP2, and phospholipase-Cβ1 (PLCβ1) in TTs in normal rat and human ventricular myocytes. PIP2 levels were reduced in spontaneously hypertensive rats during HF progression compared to age-matched controls. A PIP Strip assay of two native mouse cardiac-specific isoforms of BIN1 including the longest (cardiac BIN1 #4) and shortest (cardiac BIN1 #1) isoforms as well human skeletal BIN1 showed that all bound PIP2. In addition, overexpression of all three BIN1 isoforms caused tubule formation in HL-1 cells. A triple-lysine motif in a short loop segment between two helices was mutated and replaced by negative charges which abolished tubule formation, suggesting a possible location for PIP2 interaction aside from known consensus binding sites. Pharmacological PIP2 depletion in rat ventricular myocytes caused TT loss and was associated with changes in Ca2+ release typically found in myocytes during HF, including a higher variability in release along the cell length and a slowing in rise time, time to peak, and decay time in treated myocytes. These results demonstrate that depletion of PIP2 can lead to TT disruption and suggest that PIP2 interaction with cardiac BIN1 is required for TT maintenance and function.

Original languageEnglish (US)
Article number782767
JournalFrontiers in Physiology
StatePublished - Dec 23 2021


  • BIN-1
  • Ca transients
  • PIP2—phosphatidylinositol-4,5-bisphosphate
  • T-tubule disruption
  • heart failure

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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