Histamine Biosynthesis and Function


Histamine is one of the essential biogenic amines that mediate a wide variety of physiological and pathological responses, such as inflammation, gastric acid secretion, neurotransmission and immune modulation. Histamine is synthesised through decarboxylation of l‐histidine and functions by acting on its specific receptors consisting of H1, H2, H3 and H4 subtypes. Mast cells and basophils store histamine in their cytoplasmic granules and release it when stimulated, whereas histamine release is closely associated with its de novo synthesis in gastric enterochromaffin‐like cells, and neurons. A series of antagonists targeting H1 and H2 subtype has brought about enormous success to therapies for immediate allergy and peptic ulcer, respectively. The H3 subtype has been focused on as the therapeutic target for cognitive dysfunctions, because it is expressed preferentially in neurons and modulates the neurotransmitter release. Recently identified H4 subtype is expressed preferentially in blood cells and mediates their chemotaxis in response to histamine.

Key Concepts:

  • Histamine mediates a wide variety of physiological and pathological responses, such as inflammation, gastric acid secretion, neurotransmission and immune modulation.

  • Histamine is synthesised through decarboxylation of l‐histidine by histidine decarboxylase and is catabolised through oxidative deamination or methylation.

  • Tissue histamine levels are transiently increased by degranulation of mast cells and basophils while they are upregulated by de novo synthesis in gastric enterochromaffin‐like cells, and neurons.

  • Histamine exerts its functions by acting on its specific receptors consisting of H1, H2, H3 and H4 receptors.

  • Histamine is a paracrine mediator, of which actions are generally limited in the local microenvironment.

  • Histamine H1 receptor antagonists have brought successful therapeutic approaches for immediate allergy, because histamine evokes vasodilation and increased vascular permeability by acting on the H1 receptor.

  • In the central nervous system, histamine is involved in awakening, appetite, maintenance of circadian rhythm, learning and memory, which are regulated by the H1 and H3 receptors.

  • Histamine stimulates parietal cells to induce gastric acid secretion by acting on the H2 receptor, of which antagonists drastically improved therapeutic approaches for peptic ulcer.

  • Pre‐synaptic histamine H3 receptor regulates release of various neurotransmitters including histamine itself, and is expected as a potential drug target for the treatment of cognitive dysfunctions.

  • Histamine H4 receptor is expressed exclusively in blood cells and mediates their chemotaxis in response to histamine.

Keywords: allergy; gastric acid secretion; G protein‐coupled receptor; immunity; inflammation; neurotransmission

Figure 1.

Action of histamine. Histamine is involved in a wide variety of pathological and physiological responses, which were mediated by its specific receptor subtypes, H1, H2, H3 and H4.

Figure 2.

Cellular biosynthesis of histamine. Histidine decarboxylase (HDC) is initially translated as the precursor form, of which molecular weight is 74 kDa, and then is converted to the mature form through post‐translational processing. The 74‐kDa form is localised in the cytosol and rapidly undergoes degradation in protesomes, while the 53‐kDa form in the granules. Vesicular monoamine transporter 2 (VMAT2) mediates accumulation of histamine in the granules, whereas organic cation transporter 3 (OCT‐3) promotes release of excess amount of cytosolic histamine. In mast cells and basophils, a large amount of histamine is liberated from the granules through degranulation.

Figure 3.

Metabolism of histamine. Histamine is metabolised exclusively by methylation or oxidation. Methylation of histamine is mediated by histamine‐N‐methyltransferase (HMT), while diamine oxidase (DAO) mediates oxidative deamination of histamine to yield imidazole acetaldehyde, which is further converted to imidazole acetic acid.

Figure 4.

Immune modulation by histamine. Accumulating evidence indicates that histamine is involved in a wide variety of immune responses, such as polarisation of Th cells, proliferation of B cells, regulation of cytokine production and migration of leucocytes, in addition to inflammatory responses. B, B cell; DC, dendritic cell; EC, endothelial cell; Eos, eosinophil; NK, natural killer cell; Mac, macrophage; Mast, mast cell; SMC, smooth muscle cell; Th, helper T cell; and Treg, regulatory T cell.



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Ichikawa, Atsushi, and Tanaka, Satoshi(Apr 2012) Histamine Biosynthesis and Function. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001404.pub2]