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Phosphoinositides and PIPs01:42

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Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
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Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the  phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
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Amplifying Signals via Second Messengers01:15

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Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...
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What are Second Messengers?01:12

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Because many receptor binding ligands are hydrophilic, they do not cross the cell membrane and thus their message must be relayed to a second messenger on the inside. There are several second messenger pathways, each with their own way of relaying information. G-protein coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol path is active when the receptor induces phospholipase C to hydrolyze the phospholipid,...
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Ion channels are specialized proteins on the plasma membrane that allow charged ions to pass down their electrochemical gradient. Their main function is to maintain the membrane potential which is critical for cell viability. These channels are either gated or non-gated and can transport more than a thousand ions within milliseconds for the cellular event to occur.
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Identification of Inositol Phosphate or Phosphoinositide Interacting Proteins by Affinity Chromatography Coupled to Western Blot or Mass Spectrometry
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Phosphoinositide isoforms determine compartment-specific ion channel activity.

Xiaoli Zhang1, Xinran Li, Haoxing Xu

  • 1Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 27, 2012
PubMed
Summary
This summary is machine-generated.

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) inhibits intracellular TRPML1 channels, while PI(3,5)P(2) activates them. This phosphoinositide regulation dictates compartment-specific activity codes for membrane channels.

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Phosphoinositides act as molecular signals, directing protein localization and regulating membrane protein activity.
  • Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) is crucial for plasma membrane (PM) channel and transporter function.
  • Intracellular channels may be regulated differently than PM channels, with potential inactivation during transit through cellular pathways.

Purpose of the Study:

  • To investigate the role of phosphoinositides in modulating the activity of intracellular TRPML1 channels.
  • To determine if PI(4,5)P(2) inhibits intracellular TRPML1 channels, contrasting with its role in PM channels.
  • To elucidate the compartment-specific regulation of TRPML1 channel activity.

Main Methods:

  • Direct patch-clamping of isolated lysosomes to study lysosomal TRPML1 activity.
  • Studying PM-localized TRPML1 activity using inside-out membrane patches.
  • Manipulating PI(4,5)P(2) levels via depolarization and 5'-phosphatase translocation.
  • Site-directed mutagenesis to identify key amino acid residues in PIP(2)-interacting domains.

Main Results:

  • PM-localized TRPML1 channels, unlike lysosomal ones, are inhibited by PI(4,5)P(2).
  • Depletion of PI(4,5)P(2) or addition of PI(3,5)P(2) activates PM-localized TRPML1.
  • TRPML1 exhibits a unique run-up upon patch excision and distinct residue-mediated interactions with PI(3,5)P(2) and PI(4,5)P(2).

Conclusions:

  • PI(4,5)P(2) acts as a negative cofactor for intracellular TRPML1 channels.
  • Phosphoinositide composition provides compartment-specific activity codes for membrane proteins.
  • This regulation ensures proper channel function within distinct subcellular compartments.