Histamine is recognized by 4 organ-dependent transmembrane histamine receptors (HR), which extracellularly bind histamine and intracellularly activate specific guanosine-triphosphate-binding proteins (G proteins). HRs are monomeric proteins similarly packed in globular 3D shapes inserted into the cellular membranes through seven transmembrane α-helices connected to each other by extracellular and intracellular loops (GraphycalAbstract). Despite their 3D conformation similarity, amino acid sequences of HRs show only 20-30 % identity, and bind histamine with distinct affinities such as µM by H1R / H2R (H2R >10-fold HR1 ) or nM by H3R / H4R. Respect to their organ distribution, H1R (487 amino acid residues) is abundant in peripheral nervous system, blood vessels, muscles and gut / colon cells 20 , H2R (359 residues) is found at stomach, heart, immune cells and vascular smooth muscle, H3R (445 residues) is implicated in neurotransmitter release and H4R (390 residues) participates in immune chemotaxis.