What is the arachidonic acid pathway down to the receptor level?

Arachidonic Acid Pathway Down to the Receptor Level

The arachidonic acid pathway is a complex lipid signaling system where arachidonic acid is metabolized through three main enzymatic pathways (cyclooxygenase, lipoxygenase, and cytochrome P450) to produce bioactive eicosanoids that act on specific receptors to regulate inflammation, vascular function, and numerous physiological processes. 1, 2

Overview of Arachidonic Acid Metabolism

• Arachidonic acid (AA) is a 20-carbon polyunsaturated fatty acid normally esterified in cell membrane phospholipids and released by phospholipase A2 (PLA2) in response to various stimuli 3
• Once released, AA serves as the substrate for three major enzymatic pathways that generate distinct classes of bioactive lipid mediators 2, 3
• These metabolites act through specific G-protein-coupled receptors to mediate diverse biological effects ranging from physiological functions to pathological processes 1, 4

Major Metabolic Pathways

1. Cyclooxygenase (COX) Pathway

• Two isoforms exist: COX-1 (constitutively active) and COX-2 (inducible by inflammatory stimuli) 1, 2
• COX enzymes convert AA to unstable endoperoxide intermediates (PGG2/PGH2) 2
• These intermediates are further metabolized to:
  • Prostaglandins (PGs): PGE2, PGD2, PGF2α - vasodilatory and inflammatory mediators 1, 2
  • Prostacyclin (PGI2) - vasodilator and inhibitor of platelet aggregation 2
  • Thromboxane A2 (TXA2) - vasoconstrictor and promoter of platelet aggregation 2, 5
• COX-derived products signal through specific prostanoid receptors:
  • EP receptors (EP1-EP4) for PGE2 1
  • DP receptors for PGD2 1
  • FP receptors for PGF2α 1
  • IP receptors for PGI2 1
  • TP receptors for TXA2 1

2. Lipoxygenase (LOX) Pathway

• Multiple LOX enzymes exist, including 5-LOX, 12-LOX, and 15-LOX, each inserting oxygen at different positions of AA 2, 6
• 5-LOX, with its associated protein FLAP (5-lipoxygenase activating protein), converts AA to 5-HPETE and then to leukotrienes 6, 5
• Key products include:
  • Leukotriene A4 (LTA4) - unstable epoxide intermediate 5
  • Leukotriene B4 (LTB4) - potent neutrophil chemoattractant 5
  • Cysteinyl leukotrienes (LTC4, LTD4, LTE4) - bronchoconstrictors and mediators of vascular permeability 5
• 12-LOX produces 12-HETE, which binds to GPR31 with high affinity (Kd = 5 nM) 1
• 15-LOX generates 15-HETE and lipoxins (LXs), which are anti-inflammatory mediators 5
• Leukotrienes act through specific receptors:
  • BLT1 and BLT2 receptors for LTB4 1
  • CysLT1 and CysLT2 receptors for cysteinyl leukotrienes 1

3. Cytochrome P450 (CYP) Pathway

• CYP enzymes metabolize AA to:
  • Epoxyeicosatrienoic acids (EETs) - vasodilatory and anti-inflammatory mediators 3
  • Hydroxyeicosatetraenoic acids (HETEs) - various biological effects 2, 3
  • Dihydroxyeicosatetraenoic acids (DiHETEs) 2
• EETs are further metabolized by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids (DHETs) 3

Specialized Pro-resolving Mediators (SPMs)

• Derived from omega-3 and omega-6 polyunsaturated fatty acids, including AA 1
• Include lipoxins (from AA), resolvins, protectins, and maresins (from omega-3 fatty acids) 1
• Resolvin D1 (RvD1) has been shown to activate GPR32 with remarkably high potency (EC50 = 4 pM) 1
• SPMs actively promote resolution of inflammation without compromising host defenses 1

Receptor-Level Signaling

• Most eicosanoids act through specific G-protein-coupled receptors (GPCRs) 1, 4
• These receptors couple to different G proteins (Gs, Gi, Gq) to mediate diverse cellular responses 1
• Examples of specific receptor-ligand pairings:
  • GPR31 binds 12(S)-HETE with high affinity (Kd = 5 nM) 1
  • GPR32 binds resolvin D1 with extremely high potency 1
  • GPR18 binds N-arachidonoylglycine (NAGly), a metabolite related to endocannabinoids 1
• Receptor activation triggers various intracellular signaling cascades, including:
  • Changes in cAMP levels 1
  • Calcium mobilization 1
  • Activation of kinase pathways 1

Clinical Significance

• Dysregulation of the AA pathway is implicated in numerous pathological conditions:
  • Inflammatory diseases (arthritis, asthma) 4, 5
  • Cardiovascular disorders 3
  • Cancer development and progression 1, 3
• COX-2 expression has been demonstrated in premalignant and malignant cells, with higher levels associated with poor prognosis in non-small cell lung cancer 1
• Targeting the AA pathway has therapeutic applications:
  • NSAIDs inhibit COX enzymes, with newer agents selectively targeting COX-2 2
  • Leukotriene modifiers are used in asthma management 5
  • Novel agents targeting specific receptors or enzymes in the pathway are under development 3

Regulation of the Pathway

• Expression of key enzymes (COX, LOX) is regulated at multiple levels:
  • Transcriptional control 6
  • Alternative mRNA splicing 6
  • Alternative polyadenylation 6
  • mRNA stability 6
  • microRNA regulation 6
• These regulatory mechanisms allow for precise control of eicosanoid production in different tissues and disease states 6