Histamine is considered as one of the most important mediators of allergy and inflammation. Histamine is a chemical messenger and aminergic neurotransmitters, playing an important role in a multitude of physiological processes in central and peripheral tissues. Histamine is synthesized in a restricted population of neurons located in the tuberomammillary nucleus of the posterior hypothalamus implicated in many brain functions (e.g. sleep/wakefulness, hormonal secretion, cardiovascular control, thermoregulation, food intake, and memory formation). In peripheral tissues histamine is stored in mast cells, basophils, enterochromaffin cells. Mast cell histamine plays an important role in the pathogenesis of various allergic conditions. Histamine release leads to various well-known symptoms of allergic conditions in the skin and the airway system. Histamine-mediated effects are mediated through four pharmacologically distinct subtypes of receptors, i.e., the H1R, H2R , H3R and H4R receptors, which are all members of the G-protein coupled receptor (GPCR) family. Histamine receptors display 7 TM domains, an extracellular N-terminus, and a cytoplasmic C-terminus of variable length.

H1R (mouse 488 aa; rat 486 aa; human 487 aa, chromosome 3p21-p14; ~75-85% interspecies homology) is distributed in the brain, most smooth muscle cells, endothelial cells, adrenal medulla, and heart. H1 receptor plays roles in smooth muscle contraction, stimulation of nitric oxide formation, endothelial cell contraction, and increasing vascular permeability, all of which have close relationships with allergic conditions. H1R receptor preferentially couples to the Gq/11 family of G-proteins and causes mobilization of intracellular Ca 2+ in a pertussis toxin-insensitive fashion. Compounds such as mepyramine (also called pyrilamine) and triprolidine are highly potent H1 antagonists, and easily penetrate the brain causing sedation. Many new non-sedating H1 antagonists (e.g. cetirizine, astemizole or loratadine), are used to treat allergic conditions.

The H2R (mouse/rat 358 aa; human 359 aa chromosome 5) causes cAMP accumulation in the gastric cells, cardiac tissues, smooth muscle cells and immune cells. H2R agonists have been proven to be effective for acid peptic disorders of the GI tract. H2R is moderately expressed in the brain. H2 receptor agonist, dimaprit, is a relatively selective H2 receptor agonist with minimal H1R receptor agonism. Recently, amthamine (2-amino-5-(2-aminoethyl)-4-methylthiazole), a rigid dimaprit analog, combines a high H2R receptor selectivity. Interestingly, mutations in H2R has been linked to schizophrenia.

A third subtype of histamine receptor, human H3R (GPCR97), was finally identified as a presynaptic autoreceptor on histamine neurons in the brain controlling the stimulated release of. Subsequently, the H3 receptor has been shown to be a presynaptic heteroreceptor in nonhistamine-containing neurons in both the central and peripheral nervous systems. H3R (rat/human 445 aa, ~93% homology) is primarily expressed in the brain. Several studies using H3 selective agonists revealed that H3 receptor couples to pertussis toxin-sensitive Gi/o protein.

Most recently, a novel orphan G-protein coupled receptor, named H4R (GPRv53, human 390 aa) has been cloned and characterized. It is most closely related to H3R (~37% homology). Unlike H3R, H4R has a distinct tissue distribution and it is localized in the peripheral blood leukocytes, spleen, thymus and colon. Mammalian cells expressing H4R were demonstrated to bind and respond to histamine in a concentration-dependent manner. In functional assays, an H3 receptor agonist, R-(a)-methylhistamine, but also a H3 receptor antagonist, clobenpropit, and a neuroleptic, clozapine, activated H4R-expressing cells.