Histamine receptor

The histamine receptors are a class of G protein–coupled receptors which bind histamine as their primary endogenous ligand.^[1][2] Histamine is a neurotransmitter involved in various physiological processes. There are four main types of histamine receptors: H1, H2, H3, and H4. H1 receptors are linked to allergic responses, H2 to gastric acid regulation, H3 to neurotransmitter release modulation, and H4 to immune system function.

There are four known histamine receptors:

• H₁ receptor – Primarily located on smooth muscle cells, endothelial cells, and neurons. Activation of H1 receptors mediates various responses, including smooth muscle contraction (leading to bronchoconstriction, intestinal cramping), increased vascular permeability (resulting in edema), and stimulation of sensory nerve endings (causing itching and pain). H1 antagonists, commonly known as antihistamines, are used to alleviate symptoms of allergies and allergic reactions.^[3]
• H₂ receptor – Found mainly in the stomach lining (parietal cells), H2 receptors regulate gastric acid secretion by stimulating the production of hydrochloric acid. H2 antagonists (H2 blockers) are used to reduce stomach acid production and treat conditions like gastroesophageal reflux disease (GERD) and peptic ulcers.^[3]
• H₃ receptor – Predominantly located in the central nervous system (CNS), particularly in regions associated with neurotransmitter release and modulation. H3 receptors act as presynaptic autoreceptors and heteroreceptors, regulating the release of neurotransmitters such as dopamine, serotonin, norepinephrine, and acetylcholine. Modulation of H3 receptors is being explored as a potential target for various neurological and psychiatric disorders.^[4]
• H₄ receptor – Initially discovered on immune cells, particularly mast cells, eosinophils, and T cells, H4 receptors are involved in immune responses, including chemotaxis (cellular movement in response to chemical signals) and cytokine production. These receptors play a role in inflammation and allergic reactions. Research on H4 receptors is ongoing to better understand their involvement in immune-related disorders and to develop potential therapeutic interventions.^[5]

Comparison

Histamine receptors

Receptor	Location	Mechanism of action	Function	Antagonists	Uses of antagonists
H1	Throughout the body, especially in:[6] Smooth muscles vascular endothelial cells (cells of walls of blood vessels) adrenal medulla heart brain spinal cord	Gq	ileum contraction modulate circadian cycle itching systemic vasodilatation (indirect effect throughout the increased production of NO) bronchoconstriction (allergy-induced asthma)	H1-receptor antagonists Diphenhydramine Loratadine Cetirizine Fexofenadine Clemastine Rupatadine	Allergies nausea sleep disorders
H2	Gastric parietal cells smooth muscles mast cells neutrophils heart uterus	Gs ↑ cAMP2+	speed up sinus rhythm Stimulation of gastric acid secretion Smooth muscle relaxation Inhibit antibody synthesis, T-cell proliferation and cytokine production	H2-receptor antagonists Ranitidine Cimetidine Famotidine Nizatidine	Peptic ulcer disease Stress ulcers Gastroesophageal reflux disease Dyspepsia Aspiration pneumonia Resistant schizophrenia
H3	Thalamus caudate nucleus cerebral cortex small intestine testes prostate	Gi	Decrease Acetylcholine, Serotonin and Norepinephrine Neurotransmitter release in CNS Presynaptic autoreceptors	H3-receptor antagonists ABT-239 Ciproxifan Clobenpropit Thioperamide	Narcolepsy Alzheimer's disease Attention deficit hyperactivity disorder (ADHD) Schizophrenia
H4	Immune system lymphocytes leukocytes Lymphoid organs thymus spleen liver[7] gastrointestinal tract (GIT) pancreas bile ducts	Gi	mediate mast cell chemotaxis.[8]	H4-receptor antagonists Thioperamide JNJ 7777120	As of July 2021[update], no clinical uses exist. Potential uses include:[9] rheumatoid arthritis[10] asthma allergic rhinitis atopic dermatitis pruritus

There are several splice variants of H₃ present in various species. Though all of the receptors are 7-transmembrane g protein coupled receptors, H₁ and H₂ are quite different from H₃ and H₄ in their activities. H₁ causes an increase in PIP₂ hydrolysis, H2 stimulates gastric acid secretion, and H3 mediates feedback inhibition of histamine.