Amino acid-based mediators Histamine and 5-HT

Histamine

A basic amine derived from histidine; mediates immediate (type I) allergic and inflammatory reactions; found in many tissues with highest levels in skin, lungs, and GI; stored mainly in mast cells and basophils.

Mast cell

Tissue immune cell high in histamine; releases histamine on IgE-mediated activation or complement fragments (C3a, C5a), via Ca²⁺-dependent degranulation.

Basophil

Blood granulocyte similar to mast cells that contains and secretes histamine during allergic reactions.

Non-mast cell histamine

Histamine present in brain (as a neurotransmitter) and stomach (stimulates acid secretion) that is not primarily stored in mast cells.

Histamine receptors (H1–H4)

Four GPCR families (H1–H4) with varied tissue distributions and effects: H1 central to allergy/inflammation, H2 stimulates gastric acid secretion, H3 mainly presynaptic CNS autoreceptor, H4 in immune regulation.

H1 receptor

Gq/PLC-coupled receptor on endothelium, smooth muscle, nerve endings; mediates vasodilation, increased vascular permeability (wheal & flare), bronchoconstriction, itch, and pain.

H2 receptor

Gs-coupled receptor on gastric parietal cells (and heart); stimulates gastric acid secretion and can increase heart rate.

H3 receptor

Presynaptic autoreceptor in the CNS that modulates histamine and other neurotransmitter release.

H4 receptor

Receptor expressed on immune cells; implicated in chemotaxis and immune regulation.

Wheal and flare

Classic H1-mediated skin response: wheal = local edema from increased permeability; flare = vasodilation around the wheal.

Antihistamines (H1 antagonists / inverse agonists)

Drugs that bind H1 receptors and stabilize them in inactive conformation (inverse agonists), preventing H1-mediated symptoms (itch, vasodilation). Examples: diphenhydramine, cetirizine, loratadine.

First-generation antihistamines

Lipophilic H1 blockers (eg. diphenhydramine, hydroxyzine) that cross the BBB → sedation and anticholinergic side effects; non-selective off-target activity.

Second/third-generation antihistamines

More H1-selective agents (eg. cetirizine, loratadine, fexofenadine, levocetirizine, desloratadine) with reduced CNS penetration → less sedation and fewer autonomic side effects.

Inverse agonist (pharmacology)

A drug that binds to a receptor and shifts it toward an inactive conformation, reducing constitutive receptor activity (antihistamines act as H1 inverse agonists).

5-Hydroxytryptamine (5-HT, Serotonin)

Monoamine neurotransmitter synthesized from tryptophan and degraded by monoamine oxidase; acts as a local hormone in vasculature and neurotransmitter in CNS; found in enterochromaffin cells, platelets, and CNS neurons.

SERT (Serotonin Transporter)

High-affinity reuptake transporter in platelets and neurons that clears 5-HT from the synapse or plasma; target of SSRIs.

Physiological roles of 5-HT

Regulates vascular tone (constriction in larger vessels, dilation in arterioles), GI motility, bronchial and uterine smooth muscle contraction, platelet aggregation, and modulates nociception and mood.

Pathophysiological roles of 5-HT

Involved in migraine, carcinoid syndrome, nausea/vomiting, pulmonary hypertension, mood disorders, anxiety, and some pain states.

5-HT receptor families (5-HT1–5-HT7)

Seven receptor families with multiple subtypes; most are GPCRs except 5-HT3 which is a ligand-gated cation channel. Different families couple to different G proteins producing diverse effects.

5-HT1 family (1A, 1B, 1D, 1E, 1F)

Gi/Go-coupled GPCRs → inhibit adenylate cyclase, reduce cAMP, often act as presynaptic autoreceptors to inhibit neurotransmitter release. Key effects: neuronal inhibition, vasoconstriction (1B on cranial vessels). Drugs: 5-HT1B/1D/1F agonists (triptans) used for migraine relief via cranial vasoconstriction and trigeminal inhibition; 5-HT1A partial agonists (buspirone) used as anxiolytics.

5-HT1A

Located in limbic system and raphe nuclei; Gi-coupled; decreases cAMP; mediates anxiolytic and antidepressant effects. Drug example: buspirone (partial agonist).

5-HT1B/1D/1F

Located on cranial blood vessels and presynaptic trigeminal terminals; Gi-coupled; causes vasoconstriction and inhibits neuropeptide release. Drug examples: sumatriptan, almotriptan. Contraindicated in coronary artery disease due to vasoconstriction risk.

5-HT2 family (2A, 2B, 2C)

Gq/11-coupled → activate phospholipase C → ↑IP3/DAG → ↑Ca²⁺ and PKC activation. Found in vascular smooth muscle, platelets, and CNS. Effects: vasoconstriction, platelet aggregation, CNS excitation. Drugs: 5-HT2 antagonists (pizotifen, cyproheptadine) used in migraine prophylaxis and carcinoid symptom control. 5-HT2A activation associated with hallucinations.

5-HT2A

Located in cortex and platelets; Gq-coupled; causes cortical excitation and vasoconstriction; target for hallucinogens.

5-HT3

Ligand-gated cation channel (Na⁺/K⁺) — not GPCR. Located in chemoreceptor trigger zone, vagal afferents, and enteric neurons. Effects: excitation of vagal afferents → nausea/vomiting. Drugs: ondansetron, granisetron — antiemetics for chemotherapy/post-op nausea.

5-HT4

Gs-coupled GPCR in GI tract and CNS; increases cAMP → enhances GI motility. Drugs: prucalopride (prokinetic), tegaserod (IBS).

5-HT5

Gi-coupled; found in CNS (5-HT5A subtype); function not fully understood — may modulate mood and circadian rhythm.

5-HT6

Gs-coupled; CNS receptor (striatum, cortex, hippocampus); may influence learning and memory.

5-HT7

Gs-coupled; found in CNS and vascular smooth muscle; increases cAMP → vasodilation and circadian rhythm regulation; potential migraine and sleep regulation target.

5-HT receptor signaling summary

Gi (5-HT1) → inhibitory; Gq (5-HT2) → excitatory; ligand-gated (5-HT3) → fast depolarization; Gs (5-HT4,6,7) → stimulatory. Clinical anchors: triptans (1B/1D/1F agonists), 5-HT3 antagonists (antiemetic), 5-HT2 antagonists (migraine prophylaxis).

Migraine (phases)

Premonitory (nausea, photophobia, mood changes) → aura (visual/sensory) → headache (moderate–severe pain) → postdrome (fatigue).

Migraine theories

Vascular theory (vasoconstriction followed by dilation), cortical spreading depression, and neuroinflammation involving trigeminal activation.

Triptans

5-HT1B/1D/1F agonists used for acute migraine attacks; cause cranial vasoconstriction and inhibit trigeminal neurotransmission.

Pizotifen / Cyproheptadine

5-HT2 receptor antagonists used for migraine prophylaxis and carcinoid syndrome; cause sedation and weight gain.

Carcinoid syndrome

Tumor of enterochromaffin cells secreting 5-HT → flushing, diarrhea, bronchospasm, hypotension, cardiac valvular fibrosis. Controlled with 5-HT2 antagonists.