Histamine Biosynthesis and Function

Abstract

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 H 1 , H 2 , H 3 and H 4 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 H 1 and H 2 subtype has brought about enormous success to therapies for immediate allergy and peptic ulcer, respectively. The H 3 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 H 4 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 H 1 , H 2 , H 3 and H 4 receptors. Histamine is a paracrine mediator, of which actions are generally limited in the local microenvironment. Histamine H 1 receptor antagonists have brought successful therapeutic approaches for immediate allergy, because histamine evokes vasodilation and increased vascular permeability by acting on the H 1 receptor. In the central nervous system, histamine is involved in awakening, appetite, maintenance of circadian rhythm, learning and memory, which are regulated by the H 1 and H 3 receptors. Histamine stimulates parietal cells to induce gastric acid secretion by acting on the H 2 receptor, of which antagonists drastically improved therapeutic approaches for peptic ulcer. Pre‐synaptic histamine H 3 receptor regulates release of various neurotransmitters including histamine itself, and is expected as a potential drug target for the treatment of cognitive dysfunctions. Histamine H 4 receptor is expressed exclusively in blood cells and mediates their chemotaxis in response to histamine.