Histamine H4 receptor (HRH4) (HRH4)

The Histamine H4 receptor (HRH4) is a G protein-coupled receptor (GPCR) that is primarily expressed on cells of hematopoietic origin, including eosinophils, mast cells, dendritic cells, and T cells (UniProt: P59308). It serves as a critical mediator of histamine-induced inflammatory responses, signaling through the Gi/o protein pathway to inhibit adenylyl cyclase and increase intracellular calcium levels (PubMed: 11441016). HRH4 plays a pivotal role in the recruitment and activation of immune cells, making it a key driver in the pathogenesis of allergic and autoimmune conditions such as atopic dermatitis, asthma, and rheumatoid arthritis (PubMed: 25303113). Therapeutic development has focused on HRH4 antagonists and inverse agonists to suppress chronic inflammation and associated symptoms like pruritus. While several drug candidates, such as toreforant and zelaslo, have entered clinical trials, some have encountered challenges regarding systemic safety, specifically transient neutropenia (PubMed: 24934557). Despite these hurdles, HRH4 remains a high-priority target for inflammatory diseases where traditional H1 receptor antagonists provide insufficient relief.

Other names

H4RGPCR105GPRv53AXOR35PDRHistamine receptor H4

Antagonism or inverse agonism of the receptor inhibits Gi protein-mediated signaling, leading to decreased chemotaxis of eosinophils and mast cells and reduced production of pro-inflammatory cytokines (PubMed: 25303113).