![]() ![]() These seven-transmembrane domain GPCR proteins represent the largest family of membrane proteins in the human genome ( Jacoby et al., 2006 Lagerstrom and Schioth, 2008) and have proven to be one of the most rewarding families of drug targets to date. These biologic changes occur via four G protein–coupled receptor (GPCR) subtypes: H 1 receptor, H 2 receptor, H 3 receptor, and H 4 receptor. ![]() Histamine brings about complex physiologic changes, including neurotransmission, inflammation, smooth muscle contraction, dilatation of capillaries, chemotaxis, cytokine production, and gastric acid secretion. ![]() Histamine acts as a neurotransmitter in the nervous system and as a local mediator in the gut, skin, and immune system. Based on a sensitive high-performance liquid chromatography-mass spectrometry method, nonmast cell histamine occurs at high concentrations in enterchromaffin-like cells in the stomach, lymph nodes, and thymus, with modest levels in the liver, lung, and in varicosities of the histaminergic neurons in the brain ( Zimmermann et al., 2011). Histamine is synthesized and stored at high concentrations within granules in so called "professional" cells, basophils and mast cells, where it is associated with heparin. Histamine ( 1) is an endogenous biogenic amine distributed ubiquitously in the body being present in high concentrations in the lungs, skin, and gastrointestinal tract ( Fig. They provided the field with prototypical compounds and drugs, particularly in the H 2 receptor and H 3 receptor fields and contributed profoundly to our current understanding of histamine pharmacology. This present review is dedicated to two of the foremost histamine receptor pharmacologists, Sir James Black and Walter Schunack, who sadly died at the beginning of 20, respectively. The molecular identification of the H 3 receptor and H 4 receptor, their attendant isoforms, and species variants have now clarified to some degree the pharmacological heterogeneity reported in the 1990s, reviewed in the previous Pharmacological Reviews article by Hill et al. This has led to a massive increase in our understanding of the histamine systems in the whole body and recently resulted in the introduction of H 3 receptor and H 4 receptor drug leads into late-stage clinical development, with an ever expanding range of potential therapeutic applications. Histamine pharmacology has experienced a renaissance over the last few decades, with the identification and cloning of the histamine H 3 and H 4 receptors, which doubles the members of the histamine receptor family. ![]()
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