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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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Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
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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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Cells respond to many types of information, often through receptor proteins positioned on the membrane. They respond to chemical signals, such as hormones, neurotransmitters, and other signaling molecules, initiating a series of molecular reactions to produce an appropriate response. This is called signal transduction. Cells also coordinate different responses elicited by the same signaling molecule via mediators, allowing molecular cross-talk.
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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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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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Updated: Dec 9, 2025

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Druggable Lysophospholipid Signaling Pathways.

Keisuke Yanagida1, William J Valentine2,3

  • 1Department of Lipid Signaling, National Center for Global Health and Medicine, Tokyo, Japan. kyanagida@ri.ncgm.go.jp.

Advances in Experimental Medicine and Biology
|September 7, 2020
PubMed
Summary

Lysophosphatidic acid (LPA) signaling pathways are promising drug targets for various diseases. Targeting LPA receptors and autotaxin (ATX) shows potential for treating conditions like fibrosis and sclerosis.

Keywords:
GPCRGPR174GPR34GPR55LPILysoPSLysophosphatidylcholineLysophosphatidylglucosideP2Y10

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Cell Biology

Background:

  • Lysophosphatidic acid (LPA) is a bioactive signaling lipid with diverse physiological and pathological roles.
  • LPA exerts its effects through six G protein-coupled receptors (LPA1-6).

Purpose of the Study:

  • To review LPA signaling pathways as emerging drug targets for human diseases.
  • To discuss the therapeutic potential of targeting LPA receptors and autotaxin (ATX).
  • To explore other bioactive lysophospholipids (LPLs) as future therapeutic targets.

Main Methods:

  • Review of current literature on LPA signaling and therapeutic strategies.
  • Analysis of clinical trial data for LPA-targeting compounds.
  • Discussion of structural biology insights into LPA receptors and ATX.

Main Results:

  • LPA signaling components, including LPA receptors and ATX, are validated therapeutic targets.
  • Compounds targeting LPA signaling are in clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis.
  • Structural data for LPA receptors and ATX facilitate the development of selective inhibitors.

Conclusions:

  • LPA signaling pathways offer significant therapeutic opportunities for various diseases.
  • Other LPLs, such as lysophosphatidylserine and lysophosphatidylinositol, represent the next frontier in LPL-targeted therapies.
  • Understanding LPL production and delivery is crucial for developing effective therapeutic strategies.