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Histamine and Its Receptors

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Allergy Frontiers: Classification and Pathomechanisms

Part of the book series: Allergy Frontiers ((ALLERGY,volume 2))

Histamine is a ubiquitous mediator in the body with numerous physiological and pathological actions. In humans, there are four subtypes of histamine receptor, H1, H2, H3 and H4, all encoded on different genes. All histamine receptors are G protein-coupled receptors (GPCRs), the superfamily of which contains at least 500 individual membrane proteins that share a common structural motif of seven-transmembrane ?-helical domains arranged in a circular fashion. Interaction of histamine with a receptor stabilizes it in its active form enabling it stimulate intracellular biochemical events. Antihistamines combine with other domains of the receptor to stabilize it in its inactive form. Thus, antihistamines are inverse agonists not receptor antagonists. Stimulation of histamine H1-receptors (Gq/11-coupled GPCRs) activates two separate intracellular biochemical cascades. The first activates phospholipase C and elevates intracellular calcium to cause the immediate effects of the allergic response, including sensory nerve stimulation, mucus production and rhinorrhoea and edema. The second, acting through protein kinase C, stimulates NF- B transcription to produce cytokines and adhesion proteins. Activation of histamine H2-receptors (Gs-coupled GPCRs), in addition to stimulating gastric acid secretion, has diverse effects on the immune system including increasing IL-10 production by dendritic cells, suppressing lymphocyte responsiveness and reducing monocytes apoptosis. Most of the effects mediated histamine H2-receptors result from the elevation of intracellular cyclic AMP levels. Stimulation of histamine H3-receptors, Gi/o-coupled GPCRs which are found almost exclusively in the brain as presynaptic receptors for histamine on nerves, decreases intracellular cyclic AMP levels to reduce neuronal function. Unlike other histamine receptors, the H4-receptor, also a Gi/o-coupled GPCR, was discovered using knowledge of the human genome and sequence information of the H3-receptor. Conclusive demonstration of which cell types express the H4-receptor has been difficult because of its low level of expression and the fact that its expression appears to be controlled by inflammatory stimuli. However, H4-receptor expression has been shown particularly on dendritic cells, eosinophils and mast cells where they are suggested to increase chemotaxis and cytokine production. This suggests that the histamine H4-receptor may represent a therapeutic target for the regulation of immune function, particularly with respect to allergy and asthma.

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  1. Infection, Inflammation and Repair Research Division, South Block 825, Southampton General Hospital, Southampton, SO16 6YD, UK

    Martin K. Church

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  1. Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo, Japan

    Ruby Pawankar

  2. Southampton General Hospital, University of Southampton, Tremona Road, Southampton, UK

    Stephen T. Holgate

  3. Childrens's Mercy Hospital and Clinic, UMKC School of Medicine, 2401 Gillham Road, Kansas City, MO, 64108, USA

    Lanny J. Rosenwasser

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Church, M.K. (2009). Histamine and Its Receptors. In: Pawankar, R., Holgate, S.T., Rosenwasser, L.J. (eds) Allergy Frontiers: Classification and Pathomechanisms. Allergy Frontiers, vol 2. Springer, Tokyo. https://doi.org/10.1007/978-4-431-88315-9_21

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