InterPro: IPR008102 Histamine H4 receptor

G-protein-coupled receptors, GPCRs, constitute a vast protein family that encompasses a wide range of functions (including various autocrine, paracrine and endocrine processes). They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups. We use the term clan to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence [1]. The currently known clan members include the rhodopsin-like GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating pheromone receptors, and the metabotropic glutamate receptor family. There is a specialised database for GPCRs: http://www.gpcr.org/7tm/.

The rhodopsin-like GPCRs themselves represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [2, 3, 4].

Histamine is distributed within mast cells in all peripheral tissues and is a well-characterised mediator of inflammation and allergy. It also regulates release of gastric acid from parietal cells in the gastric mucosa. A fourth member of the histamine receptor family, HH4R, has been identified that is expressed primarily in cells and tissues of the immune system, including: peripheral blood leukocytes, bone marrow, spleen and thymus [5]. This expression pattern suggests that the receptor may represent a novel therapeutic target for the regulation of immune function, particularly in allergy and asthma. Binding of histamine to HH4R appears to result in inhibition of forskolin-stimulated cAMP accumulation through coupling to Gi proteins. The receptor has also been found to have a relatively high level of constitutive activity.