Browsing Pathways

Histamine is a ubiquitous messenger molecule released from mast cells, basophils, enterochromaffin-like cells, and neurons. Its various actions are mediated by histamine receptors H1, H2, H3, and H4. Histamine receptor H1 belongs to the family of G-protein-coupled receptors (GPCRs), and it is expressed in smooth muscles, on vascular endothelial cells, in the heart, and in the central nervous system. It is linked to an intracellular G-protein (Gαq) that activates phospholipase C and the phosphatidylinositol (PIP2) signalling pathway which promotes inflammatory processes through calcium ion release and expression of the NF-κB immune response transcription factor. H1-antihistamines inactivate the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Upon binding by histamine, the H1 receptor allosterically activates the G-protein by exchanging GDP for GTP at the G-protein's alpha subunit (Gαq). This results in the dissociation of a Gαq-GTP monomer and a Gβγ dimer from the receptor . Gαq-GTP activates phospholipase C-beta which cleaves the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) into the secondary messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 diffuses through the cytoplasm to the ER and binds to the inositol 1,4,5-trisphosphate (Ins3P) receptor, releasing calcium from the endoplasmic reticulum into the cytoplasm. An increase in the calcium concentration results in increased mediator release and decreased mast cell stability. Both calcium and DAG activate the kinase activity of protein kinase C beta (PKC). Among many other functions, PKC activates NF-κB. This leads to increased antigen presentation and increased expression of pro-inflammatory cytokines, cell adhesion molecules, and chemotactic factors.