Apart from its known function, the plasma membrane Ca2+atpase can regulate Ca2+ signaling by controlling phosphatidylinositol 4,5-bisphosphate levels

John T. Penniston, Rita Padányi, Katalin Pászty, Karolina Varga, Luca Hegedűs, Agnes Enyedi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Plasma membrane Ca2+ ATPases (PMCAs, also known as ATP2B1-ATP2B4) are known targets of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], but if and how they control the PtdIns(4,5)P2 pool has not been considered. We demonstrate here that PMCAs protect PtdIns(4,5)P2 in the plasma membrane from hydrolysis by phospholipase C (PLC). Comparison of active and inactive PMCAs indicates that the protection operates by two mechanisms; one requiring active PMCAs, the other not. It appears that the mechanism requiring activity is the removal of the Ca2+ required for sustained PLC activity, whereas the mechanism not requiring activity is PtdIns(4,5)P2 binding. We show that in PMCA overexpressing cells, PtdIns(4,5)P2 binding can lead to less inositol 1,4,5-triphosphate (InsP3) and diminished Ca2+ release from intracellular Ca2+ pools. Inspection of a homology model of PMCA suggests that PMCAs have a conserved cluster of basic residues forming a 'blue collar' at the interface between the membrane core and the cytoplasmic domains. By molecular dynamics simulation, we found that the blue collar forms four binding pockets for the phosphorylated inositol head group of PtdIns(4,5)P2; these pockets bind PtdIns(4,5)P2 strongly and frequently. Our studies suggest that by having the ability to bind PtdIns(4,5)P2, PMCAs can control the accessibility of PtdIns(4,5)P2 for PLC and other PtdIns(4,5)P2-mediated processes.

Original languageEnglish
Pages (from-to)72-84
Number of pages13
JournalJournal of cell science
Volume127
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

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Keywords

  • Molecular dynamics simulation
  • Phosphatidylinositol 4,5,-bisphosphate
  • Pmca

ASJC Scopus subject areas

  • Cell Biology

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