Study Notes for BIOL2048: Histamine and 5-HT

Key References

Naunyn-Schmiedeberg's Archives of Pharmacology
Pohar & Hansson (2020)

Pharmacologist Nobel Prize Laureates in Physiology or Medicine

Year	Name	Motivation
1936	Otto Loewi, Sir Henry Hallett Dale	For discoveries relating to chemical transmission of nerve impulses
1938	Corneille Jean Fran'ois Heymans	For the discovery of the role of sinus and aortic mechanisms in respiration regulation
1939	Gerhard Domagk	For discovery of antibacterial effects of prontosil
1950	Edward Calvin Kendall, Tadeus Reichstein, Philip Showalter Hench	For discoveries relating to hormones of adrenal cortex and their effects
1957	Daniel Bovet	For discoveries relating to synthetic compounds affecting body substances, especially vascular system
1970	Ulf von Euler, Julius Axelrod, Sir Bernard Katz	For discovering humoral transmitters mechanisms
1982	John R. Vane, Bengt I. Samuelsson, Sune K. Bergström	For discoveries concerning prostaglandins and related substances
1988	Sir James W. Black, Gertrude B. Elion, George H. Hitchings	For principles of drug treatment
1992	Edwin G. Krebs, Edmond H. Fischer	For discoveries in reversible protein phosphorylation as biological regulatory mechanisms
1994	Alfred G. Gilman, Martin Rodbell	For discovery of G-proteins and their role in cell signal transduction
1998	Robert F. Furchgott, Louis J. Ignarro, Ferid Murad	For discoveries concerning nitric oxide as signaling molecule in cardiovascular system
2000	Arvid Carlsson, Paul Greengard, Eric R. Kandela	For signal transduction discoveries in the nervous system
2015	Tu Youyou	For novel malaria therapy

Learning Outcomes

By the end of this session, students should be able to:

Explain the synthesis and metabolism of histamine & 5-hydroxytryptamine (5-HT).
Analyze their actions on specific receptor subtypes within the periphery and the Central Nervous System (CNS).
Identify clinical applications of drugs targeting these systems.

Histamine and 5-HT Overview

Biogenic Amines: Both molecules are low molecular weight ( $MW \approx 100$ ) nitrogenous compounds.
Autacoids: Derived from the Greek "autos" (self) and "acos" (remedy). They act as local hormones, synthesized and released locally to act on nearby cells.
Dual Roles: They serve as both peripheral mediators (inflammation, gastric acid) and crucial neurotransmitters in the CNS.

1. Histamine

1.1 Structure and Chemical Properties

Chemical Name: 2-(4-imidazole)ethylamine.
Composition: An imidazole ring attached to an ethylamine side chain.
Ionization State:
- Imidazole ring $pK_a = 5.74$ : Primarily uncharged at physiological pH ( $7.4$ ).
- Side-chain amino group $pK_a = 9.8$ : Highly protonated and positively charged at pH $7.4$ .
- Tautomerism: Histamine exists as two tautomers (ne-H and nt-H), which is significant for receptor binding specificity.

1.2 Synthesis and Metabolism

Synthesis:
- Precursor: L-Histidine (essential amino acid).
- Enzyme: L-histidine decarboxylase (HDC). This requires pyridoxal phosphate (Vitamin $B_6$ ) as a cofactor.
- Locations: Mast cells, basophils, histaminergic neurons (tuberomammillary nucleus of the hypothalamus), and enterochromaffin-like (ECL) cells in the stomach.
Metabolism:
- Pathway A (Major in CNS): Histamine is methylated by Histamine N-methyltransferase (HNMT) to N-methylhistamine, then oxidized by MAO-B to N-methylimidazole acetic acid.
- Pathway B (Peripheral): Oxidative deamination by Diamine Oxidase (DAO) to imidazole acetic acid (often excreted as riboside conjugates).

1.3 Storage and Release

Mast Cell Storage: Stored in granules in a complex with heparin (acidic proteoglycan) and proteins. This ionic binding keeps histamine inactive until release.
Release Mechanisms:
1. Immunological (Type I Hypersensitivity): IgE antibodies bind to $Fc\epsilon RI$ receptors. Allergen cross-linking triggers $Ca^{2+}$ influx and exocytosis.
2. Chemical/Mechanical: Basic drugs (e.g., morphine, tubocurarine), physical trauma, cold, or UV light can cause non-receptor-mediated degranulation.

1.4 Histamine Receptors and Physiological Actions

All four known histamine receptors are G-Protein Coupled Receptors (GPCRs).

Receptor	G-Protein	Primary Locations	Major Effects
$H_1$	$G_q$	Smooth muscle, endothelium, CNS	Vasodilation (via NO), increased permeability (edema), bronchoconstriction, pain/itching.
$H_2$	$G_s$	Gastric parietal cells, cardiac muscle	Stimulates gastric acid secretion, increases heart rate/contractility.
$H_3$	$G_{i/o}$	CNS (presynaptic)	Autoreceptor: inhibits histamine release. Heteroreceptor: inhibits release of ACh, NE, 5-HT.
$H_4$	$G_{i/o}$	Bone marrow, leukocytes	Chemotaxis of eosinophils and mast cells; modulates immune response.

2. 5-Hydroxytryptamine (5-HT / Serotonin)

2.1 Synthesis and Metabolism

Synthesis Pathway:
- Precursor: L-Tryptophan.
- Step 1 (Rate-limiting): Tryptophan is hydroxylated by tryptophan hydroxylase (TPH) to 5-hydroxytryptophan (5-HTP).
- Step 2: 5-HTP is decarboxylated by aromatic L-amino acid decarboxylase to 5-HT.
Metabolism:
- Primarily catalyzed by Monoamine Oxidase (MAO), specifically MAO-A.
- Product: 5-Hydroxyindole acetic acid (5-HIAA), which is excreted in urine and used as a clinical marker for serotonin-secreting tumors (carcinoid syndrome).

2.2 Distribution and Storage

Enterochromaffin (EC) cells: 90% of total body 5-HT is found in the GI tract, regulating motility.
Platelets: Do not synthesize 5-HT but sequester it from plasma via the Serotonin Transporter (SERT).
CNS: Synthesized in the Raphe Nuclei of the brainstem, projecting widely to modulate mood, sleep, and appetite.

2.3 5-HT Receptor Overview

There are 7 families (5-HT1 $to$ 5-HT7) comprising at least 14 subtypes. Most are GPCRs, except for $5-HT_3$ , which is a ligand-gated ion channel ( $Na^+/K^+$ ).

5-HT{1A/1B/1D} $($ Gi): Inhibitory. Triptans (agonists) are used for migraines to cause cerebral vasoconstriction.
5-HT2 (Gq): Excitatory. Involved in platelet aggregation and smooth muscle contraction.
$5-HT_3$ (Ionotropic): Located in the area postrema (chemoreceptor trigger zone). Antagonists (e.g., Ondansetron) are potent anti-emetics.
5-HT4 (Gs): Increases GI motility (prokinetic effect).

3. Clinical Implications and Diseases

Anaphylaxis: Massive systemic histamine release treated with Epinephrine (physiological antagonist).
Peptic Ulcer Disease: Use of $H_2$ antagonists (e.g., Cimetidine, Ranitidine) to reduce gastric acid output.
Depression: Linked to low synaptic 5-HT levels. Treated with Selective Serotonin Reuptake Inhibitors (SSRIs) like Fluoxetine.
Migraine: Involves dysregulation of 5-HT in cranial blood vessels.