[Frontiers in Bioscience 17, 2089-2106, June 1, 2012]

Molecular pharmacology of histamine H4 receptors

Saskia Nijmeijer1, Chris de Graaf1, Rob Leurs1, Henry F. Vischer1

1VU University Amsterdam, Leiden-Amsterdam Center for Drug Research, De Boelelaan 1083, 1081HV Amsterdam, The Netherlands


1. Abstract
2. Introduction/history
3. H4R gene
4. H4R expression profile
5. H4R protein structure and post-translational modifications
5.1. H4R assembly in the cell membrane
6. H4R ligands
6.1. H4R agonists
6.2. H4R antagonists / inverse agonists
6.3. H4R radioligands
7. Elucidation of ligand binding modes in H4R
7.1. Species differences
7.2. Binding pockets in H4R
7.3. Binding mode of histamine
7.4. Binding mode of JNJ 7777120
8. Signaling of H4R
8.1. Calcium mobilization
8.2. Migration
8.3. Modulation of protein expression and physiological effects regulated by H4R
8.4. Beta-arrestin recruitment to H4R / Biased agonism
9. Final remarks
10. Acknowledgements
11. References


The histamine H4 receptor (H4R) is the youngest member of the histamine receptor family. Based on its predominant expression pattern in hematopoietic cells, the H4R is considered to be an interesting drug target for inflammatory disorders such as allergy and asthma. Since the identification and cloning of the H4R in 2000, drug discovery programs boosted the development of various H4R (specific) ligands. Differences between H4R orthologs in combination with available three-dimensional G protein-coupled receptor (GPCR) models have guided site-directed mutagenesis studies to gain insight in ligand binding and receptor activation. In addition, ongoing characterization of H4R-mediated signaling in transfected and native cells contributes to further unravel the (patho-) physiological functions of H4Rs.