Eicosanoids Overview and Functions

Major Classes of Eicosanoids

• Prostaglandins
• Thromboxanes
• Prostacyclins
• Leukotrienes
• HETEs

Synthesis of Eicosanoids

• Diacylglycerol or phospholipid are precursors for arachidonic acid
• Arachidonic acid is released from phospholipids by phospholipases
• Arachidonic acid is then converted to prostaglandins, thromboxanes, prostacyclins, and leukotrienes through different enzymes
• COX (Cyclooxygenase) enzymes, Lipoxygenases, Glutathione-S-transferase are involved in the pathway.
• Different enzymes are responsible for the formation of each eicosanoid.

Effects of Eicosanoids

• Induce inflammation
• Mediate pain signals
• Induce fever
• Cause smooth muscle contraction (including the uterus)
• Cause smooth muscle relaxation
• Protect the stomach lining
• Stimulate platelet aggregation
• Inhibit platelet aggregation
• Cause sodium and water retention

Clinical Relevance

• Elevated eicosanoids contribute to inflammation and pain.
• NSAIDs, corticosteroids, disease-modifying antirheumatic drugs (DMARDs) and lifestyle modifications can help modulate the eicosanoid pathway.

Synthesis of Hormone Derivatives of Tryptophan

• L-Tryptophan is converted to 5-hydroxytryptophan
• 5-hydroxytryptophan is converted to serotonin and then
• Serotonin is converted to N-acetylserotonin which further is converted
• N-acetylserotonin is converted to melatonin

Synthesis of Hormone Derivatives of Tyrosine

• Tyrosine is converted to DOPA
• DOPA is converted to Dopamine
• Dopamine is converted to Noradrenaline
• Noradrenaline is converted to Adrenaline

Synthesis of Hormone Derivatives of Tyrosine

• Tyrosine can be iodinated to form thyroxine (T4) and triiodothyronine (T3).

Transport of Hormones

• Peptide/protein hormones: dissolve easily in plasma, but still bound to carrier proteins.
• Steroid/amine hormones: mostly bound to proteins in plasma, resulting in a relatively low concentration of free hormones.
• Free (unbound) hormones are biologically active.

Binding Hormones

• Specialized binding proteins: High affinity, low capacity, present in small amounts (e.g. CBG, TBG).
• Non-specialized binding proteins: Low affinity, high capacity, binds steroids and thyroid hormones (e.g. plasma albumins).

Consequences of Binding

• Prevents overaction of hormone
• Prolongs hormone effect
• Prevents large fluctuations in active hormone levels
• Increases total hormone-carrying capacity of blood

Hormone Concentration in Blood

• Peptide hormones have low levels (e.g., 10⁻¹² to 10⁻⁹ M)
• Steroid hormones have much higher levels (e.g., 10⁻⁷ to 10⁻¹⁰ M)
• Aldosterone is an exception, very low level

Patterns of Hormone Secretion

• Chronic: relatively constant concentration over time
• Acute: in response to a stimulus
• Episodic/Cyclic: fluctuating concentration over time

Hormone Specificity

• Hormones affect only target tissues with specific receptors.
• Receptor numbers are not constant; they are regularly degraded and replaced.
• Downregulation: decrease in synthesis of receptors after prolonged exposure, making targets less sensitive to the hormone.
• Upregulation: increase in synthesis of receptors after prolonged low exposure, making targets more sensitive to the hormone.

Receptor Location – Protein/Peptide Hormones

• Receptors are located on the plasma membrane
• Extracellular domains: exposed to the exterior, bind the hormone (ligand).
• Transmembrane domains: span the membrane, providing structural support.
• Cytoplasmic or intracellular domain interacts with intracellular molecules generating signals and triggering responses
• Ligand-Binding domain, Transmembrane domains, Extracellular domain

cAMP Second Messenger System

• Hormones bind to receptors activating G protein.
• G protein activates adenylate cyclase.
• Adenylate cyclase converts ATP to cyclic AMP (cAMP).
• cAMP activates protein kinase.
• Protein kinase initiates various cellular responses.

Turning off the signal:

• Gα hydrolyzes GTP to GDP+Pi, thus inactivating G protein, thereby stopping the cycle.
• Phosphodiesterases catalyze the hydrolysis of cAMP to AMP terminating the second messenger signal.

Various Cellular Responses from cAMP

• Cellular responses include: enzyme secretion, lipid breakdown, glycogen synthesis, glycogen breakdown.

other protein hormone receptors

• Trans-membrane receptor tyrosine kinases such as insulin and growth factors.
• Activation of intracellular signal pathways.
• Dimerization and autophosphorylation (in many cases).

Steroid Hormone Action

• Steroid hormones diffuse across the plasma membrane due to their lipid solubility.
• Steroid hormones bind to intracellular receptors.
• Hormone-receptor complex binds to DNA.
• Changes gene expression.
• New proteins are synthesized resulting in a particular cellular response.

Thyroid Hormone Nuclear Receptor

• Thyroid hormone (T3 and T4) bind to intracellular receptors.
• Hormone-receptor complex binds to DNA, triggering changes in gene expression.
• Synthesis of new proteins leading thyroid response.

Hormones to Act Via cAMP

• Adrenocorticotropic hormone (ACTH), Follicle stimulating hormone (FSH), Luteinizing hormone (LH), Thyroid stimulating hormone (TSH), Chorionic Gonadotropins (hCG), ß endorphins and enkephalins, Antidiuretic hormone (ADH), Glucagon, parathyroid hormone (PTH), Calcitonin, Epinephrine, Norepinephrine also act through cAMP second messenger system

Hormones to Act Via cGMP

• Atrial Natriuretic Factor (ANF), Nitric Oxide (NO)

ACT Via Phosphotydyl Inositol/Calcium

• Thyrotropin releasing hormone (TRH), Gonadotropin-releasing hormone (GnRH), Gastrin, Cholecystokinin (CCK).

Known to Act Via Tyrosine Kinase/Phosphatase Cascade

• Insulin, Growth hormone (GH), Prolactin (PRL), Oxytocin, insulin-like growth factors (IGF-1, IGF-II)

This quiz covers the major classes of eicosanoids, their synthesis pathways, and their physiological effects. You'll learn about the roles of different enzymes in eicosanoid metabolism and their clinical significance, particularly in relation to inflammation and pain management. Test your knowledge on these vital compounds and their implications in health and disease.