Difficulty: Intermediate | Prerequisites: Part 1 (Intercellular Communication Mechanisms), basic organic chemistry (amino acids, lipids, cholesterol structure).
Part 1 introduced the broad categories of chemical messengers. This set of notes goes deeper into each messenger class: how each is synthesised, stored, released, and transported through the body. The synthesis and transport rules follow directly from a messenger's chemical structure (lipophilic vs. lipophobic), so the pattern from Part 1 keeps paying off here. This material is essential groundwork for understanding drug mechanisms (e.g. why aspirin works, why caffeine makes you jittery) and for the signal transduction detail in Part 3.
The body uses five main chemical classes of messenger: amino acids, amines, peptides/proteins, steroids, and eicosanoids. Each class has a distinct synthesis pathway and transport mechanism. Hydrophilic messengers travel freely in blood but cannot cross membranes; lipophilic messengers ride carrier proteins in blood but diffuse straight through membranes.
Catecholamines
A subgroup of amine messengers derived from tyrosine, including dopamine, norepinephrine, and epinephrine. In simple terms, these are the "fight-or-flight" chemicals.
Tyrosine hydroxylase
The rate-limiting enzyme in catecholamine synthesis. It converts tyrosine to L-DOPA, the first committed step in making dopamine, norepinephrine, and epinephrine.
Decarboxylase
An enzyme that removes a carboxyl group from an amino acid during amine synthesis. It converts L-DOPA to dopamine, for example.
Prepropeptide
The initial, unprocessed form of a peptide messenger as it is first translated on ribosomes in the rough ER. Think of it as the raw draft before editing.
Propeptide
The intermediate form after the signal sequence is cleaved from the prepropeptide. Further processing in the Golgi produces the mature, active peptide.
Exocytosis
The process by which a vesicle fuses with the plasma membrane and releases its contents into the extracellular space. This is the main secretion mechanism for hydrophilic messengers.
Arachidonic acid
A 20-carbon polyunsaturated fatty acid found in cell membrane phospholipids. It is the precursor for all eicosanoids.
Cyclooxygenase (COX)
The enzyme that converts arachidonic acid into prostaglandins, prostacyclins, and thromboxanes. This is the enzyme that aspirin inhibits.
Lipoxygenase
The enzyme that converts arachidonic acid into leukotrienes, which mediate inflammation and allergic responses.
Prostaglandins
Eicosanoid paracrines produced via the COX pathway. They play roles in inflammation, pain, fever, and blood clot regulation.
Thromboxanes
Eicosanoids produced via the COX pathway that promote platelet aggregation and blood clotting.
Leukotrienes
Eicosanoids produced via the lipoxygenase pathway, involved in allergic and inflammatory responses (e.g. bronchoconstriction in asthma).
Carrier protein (transport protein)
A blood plasma protein that binds lipophilic messengers during circulation, protecting them from degradation and keeping them in an inactive, reservoir form. More than 99% of circulating steroids and thyroid hormones are protein-bound.
Certain amino acids double as neurotransmitters in the central nervous system.
Excitatory neurotransmitters
Glutamate: the main excitatory neurotransmitter in the CNS.
Aspartate: also excitatory, less commonly tested.
Inhibitory neurotransmitters
GABA (gamma-aminobutyric acid): the main inhibitory neurotransmitter in the brain.
Glycine: inhibitory neurotransmitter in the spinal cord.
Synthesis and release
Synthesised within neurons (not obtained directly from dietary amino acids).
Produced in the cytosol.
Packaged into synaptic vesicles and released by exocytosis upon stimulation.
Amines are derived from amino acids by enzymatic modification, mainly from tyrosine or tryptophan.
Key amines and their primary roles
Dopamine: mainly a neurotransmitter (CNS reward, motor control).
Norepinephrine: primarily a neurotransmitter (sympathetic nervous system).
Epinephrine: mainly a hormone (released from the adrenal medulla into the blood).
Serotonin: neurotransmitter affecting mood, sleep, appetite. Derived from tryptophan.
Histamine: a paracrine involved in inflammation and allergic responses.
Synthesis pathway
Tyrosine is converted stepwise into dopamine, then norepinephrine, then epinephrine.
Key enzymes: tyrosine hydroxylase (rate-limiting), decarboxylase, dopamine beta-hydroxylase.
Most amines are stored in vesicles and released by exocytosis.
The thyroid hormone exception
Thyroid hormones (T3 and T4) are classified as amines because they derive from tyrosine.
Unlike other amines, they are lipophilic.
They cross the plasma membrane and bind intracellular receptors to influence gene transcription.
Synthesised in the thyroid gland, not in vesicles like other amines.
This is the largest class of chemical messenger in the body.
Size distinction
Peptides: fewer than 50 amino acids.
Proteins: 50 or more amino acids.
Characteristics
Hydrophilic, so they cannot cross cell membranes.
Must bind membrane receptors (G protein-coupled, enzyme-linked, or channel-linked).
Synthesis pathway (important sequence to know)
Gene is transcribed and translated on ribosomes of the rough ER as a prepropeptide.
Signal sequence is cleaved, producing a propeptide.
Further processing in the Golgi apparatus produces the mature, active peptide or protein.
Stored in secretory vesicles until a stimulus triggers exocytosis.
Functional note
Because they bind membrane receptors, peptide/protein messengers trigger rapid intracellular responses (enzyme activation, ion channel opening) without the messenger itself entering the cell.
Steroid hormones are derived from cholesterol.
Properties
Lipophilic: diffuse freely across cell membranes.
Receptors are intracellular (cytosol or nucleus).
Regulate gene expression by binding nuclear hormone receptors, leading to transcriptional changes.
Synthesis
Occurs in the smooth endoplasmic reticulum or mitochondria.
Cannot be stored in vesicles (they would simply diffuse out through the vesicle membrane), so they are synthesised on demand and released immediately.
Examples
Cortisol (stress response, metabolism).
Aldosterone (sodium and water balance).
Testosterone, oestrogen, progesterone (sex steroids, reproductive function).
Eicosanoids are lipid-based paracrine signals derived from arachidonic acid in cell membranes.
General features
Produced by most cells upon activation (not just specialised glands).
Act locally as paracrines.
Involved in inflammation, blood flow regulation, and clotting.
Two main biosynthetic pathways
COX (cyclooxygenase) pathway: produces prostaglandins, prostacyclins, and thromboxanes.
Lipoxygenase pathway: produces leukotrienes.
Functions
Prostaglandins: inflammation, pain sensitisation, fever, and regulation of blood clot formation.
Thromboxanes: promote platelet aggregation.
Leukotrienes: mediate allergic and inflammatory responses, cause bronchoconstriction.
Clinical notes
Aspirin inhibits COX enzymes, reducing prostaglandin and thromboxane synthesis. This alleviates pain and inflammation but can cause stomach irritation (because protective prostaglandins in the stomach lining are also reduced).
COX-2 inhibitors selectively block the inflammatory COX isoform, sparing the protective COX-1 pathway and reducing gastrointestinal side effects.
How a messenger travels through the body depends entirely on whether it is hydrophilic or lipophilic.
Hydrophilic messengers (amino acids, peptides, catecholamines)
Secreted by exocytosis.
Dissolve freely in blood plasma (fewer than 1% are protein-bound).
Short half-life: rapidly degraded by enzymes or cleared by the kidneys.
Lipophilic messengers (steroids, thyroid hormones, eicosanoids)
Diffuse directly across cell membranes (no exocytosis needed for release).
Bind to carrier proteins in the blood (more than 99% are protein-bound at any given time).
Longer half-life: the carrier protein protects them from degradation.
Only the unbound (free) fraction is biologically active.
Aspirin's mechanism is a direct application of eicosanoid biology: by inhibiting COX, it reduces prostaglandin-mediated pain and thromboxane-mediated clotting (which is why low-dose aspirin is used to prevent heart attacks). Understanding the carrier-protein system explains why certain blood tests measure "free" vs. "total" hormone levels, as in thyroid function panels: only the free fraction tells you what is actively signalling.
Students often think amino acid neurotransmitters come directly from food. They do not. Neurons synthesise glutamate, GABA, and glycine internally; dietary amino acids are precursors but are not used as-is.
Epinephrine and norepinephrine are often assumed to be interchangeable. They are not. Norepinephrine is primarily a neurotransmitter (released at sympathetic nerve endings), while epinephrine is primarily a hormone (released from the adrenal medulla into the blood).
Students sometimes believe steroids are stored in vesicles like peptides. Steroids are lipophilic and would leak through any membrane, so they are synthesised on demand and released immediately.
"Carrier protein" does not mean the protein delivers the messenger to the receptor. The bound messenger is inactive. The carrier protein is a reservoir and a shield against degradation. Only the free fraction acts on target cells.
⚠️ The prepropeptide, propeptide, mature peptide synthesis sequence is commonly tested. Know the organelles involved at each stage (rough ER, Golgi, secretory vesicle).
⚠️ Be prepared to explain why steroids cannot be stored and must be synthesised on demand (lipophilic molecules diffuse through vesicle membranes).
⚠️ The COX pathway and aspirin's mechanism of action appear frequently. Know which products come from COX vs. lipoxygenase.
⚠️ Expect a question on the transport differences between hydrophilic and lipophilic messengers, including protein-binding percentages and half-life implications.
⚠️ Thyroid hormones as a lipophilic exception among amines remains high-yield here as well.
True or False: Prostaglandins are produced by the lipoxygenase pathway.
False. Prostaglandins are produced by the COX (cyclooxygenase) pathway. Leukotrienes come from the lipoxygenase pathway.
Fill in the blank: The rate-limiting enzyme in catecholamine synthesis is __________.
Tyrosine hydroxylase.
True or False: Steroid hormones are stored in secretory vesicles until needed.
False. Steroids are lipophilic and cannot be stored in vesicles. They are synthesised on demand.
Fill in the blank: More than 99% of circulating lipophilic messengers are bound to __________ in the blood.
Carrier proteins (transport proteins).
True or False: Peptide messengers are synthesised first as prepropeptides in the rough ER.
True.
Q: Trace the synthesis pathway of a peptide hormone from gene to secretion.
A: The gene is transcribed and translated on rough ER ribosomes as a prepropeptide. The signal sequence is cleaved to form a propeptide. The propeptide is processed in the Golgi into the mature peptide, packaged into secretory vesicles, and released by exocytosis upon stimulation.
Q: Why does aspirin cause stomach irritation?
A: Aspirin inhibits COX enzymes non-selectively. This reduces not only inflammatory prostaglandins but also the protective prostaglandins that maintain the stomach lining's mucus barrier, increasing the risk of irritation and ulceration.
Q: Compare the transport of insulin (a peptide hormone) with cortisol (a steroid hormone) in the bloodstream.
A: Insulin is hydrophilic, dissolves freely in plasma, has a short half-life, and fewer than 1% of its molecules are protein-bound. Cortisol is lipophilic, binds carrier proteins in the blood (more than 99% bound), has a longer half-life, and only its free fraction is biologically active.
Q: Name the three catecholamines and state the amino acid precursor they are all derived from.
A: Dopamine, norepinephrine, and epinephrine. All are derived from tyrosine.
Q: What distinguishes eicosanoids from other lipophilic messengers in terms of their range of action?
A: Eicosanoids act as paracrines (locally, on nearby cells), whereas most other lipophilic messengers (e.g. steroid hormones) travel through the bloodstream to act on distant targets.
The COX/lipoxygenase pathways connect to pharmacology (NSAIDs, COX-2 inhibitors, leukotriene receptor antagonists used in asthma). Peptide hormone synthesis ties into your understanding of the endomembrane system (rough ER, Golgi, vesicle trafficking) from cell biology. Catecholamine signalling is central to the autonomic nervous system unit. Steroid hormone gene regulation connects to molecular biology and the endocrine system.
amino acid neurotransmitters, glutamate, GABA, glycine, aspartate, amine messengers, catecholamines, dopamine, norepinephrine, epinephrine, serotonin, histamine, tyrosine hydroxylase, decarboxylase, thyroid hormones T3 T4, peptide hormones, protein hormones, prepropeptide, propeptide, rough ER, Golgi apparatus, exocytosis, steroid hormones, cholesterol, cortisol, aldosterone, testosterone, oestrogen, progesterone, eicosanoids, arachidonic acid, cyclooxygenase, COX, lipoxygenase, prostaglandins, thromboxanes, leukotrienes, aspirin mechanism, COX-2 inhibitors, carrier proteins, transport proteins, hydrophilic transport, lipophilic transport, anatomy and physiology, A&P study notes