Histamine is considered as one of the most important immunomodulator molecules owing to being a mediator of allergy and inflammation processes. Moreover, histamine is a chemical messenger and aminergic neurotransmitter, playing an important role in a multitude of physiological processes in the central nervous system and peripheral tissues. Histamine is synthesized in a restricted population of neurons located in the tuberomammillary nucleus of the posterior hypothalamus implicated in many brain functions (e.g., sleep/wakefulness, hormonal secretion, cardiovascular control, thermoregulation, food intake, and memory formation). In peripheral tissues, histamine is stored in mast cells, basophils and enterochromaffin cells. Mast cell histamine plays an important role in the pathogenesis of various allergic conditions, e.g., histamine release leads to various well-known symptoms of allergic conditions in the skin and the airway system. Histamine can influence the tumor cell proliferation and promotion directly as a growth factor, e.g., in colon tumor, gastric tumor and melanoma, and indirectly via the modification of, e.g., cytokine production in the tumor and in the tumor-surrounding environment.
Histamine is formed from L-histidine by histidine-decarboxylase enzyme (HDC) and it is degradated by two enzymes, the diamino-oxidase (DAO) and the histamine-N-metyl transferase (HNMT). In the nasal mucosa HNMT seems to be responsible for the degradation. Histamine induces IL-5 production in Th2 cells through H2 receptors.
Fig. 1 Histamine metabolism.
The effects of histamine are mediated through four pharmacologically distinct subtypes of receptors, i.e., the H1, H2, H3, and H4 receptors, which are all members of the G-protein coupled receptor (GPCR) family. Histamine receptors display seven transmembrane (TM) domains, which are predicted to form helices that span the cell membrane, an extracellular N-terminus and a cytoplasmic C-terminus of variable length. The third and fifth TM domains of the receptors appear to be responsible for ligand binding, while the third intracellular loop is responsible for signaling pathway connection. Interestingly, the genes encoding the H1, H2, and H3 receptors share less protein sequence identity with each other than with other biogenic amine receptor family members, e.g., with M2 muscarinergic receptor. Their overall homology is low (average 38%), suggesting that these histamine receptors evolved from different ancestor sequences.50 Although lacking significant overall sequence homology, the histamine receptors apparently acquired crucial elements for the recognition of histamine during their evolution, e.g., in their ligand binding region.
Human H1 receptor (H1R) is composed of 487 amino acids and showed ~75– 85% interspecies homology. H1 receptor preferentially couples to the Gq/11 family of G-proteins and causes mobilization of intracellular Ca2+ in a pertussis toxin (PTX)-insensitive fashion. Histamine activates phospholipase C (PLC), which mediates the cleavage of the membrane phosphatidyl inositol diphosphate (PIP2), which results in formation of inositol triphosphate (IP3) and 1,2-diacyl glycerol (DAG). IP3 in turn mediates Ca2+ release from endoplasmic reticulum, and also increases Ca2+ influx from the extracellular space as a secondary but longer lasting event. This latter effect can be inhibited by nifedipine, suggesting the involvement of an L-type voltage-dependent Ca2+ ion channel. As a consequence of Ca2+ ion influx, a secondary breakdown of membrane phosphoinositides occurs. IP3 can be phosphorylated to produce IP4 which further increases the intracellular Ca2+ level. DAG activates a serine/threonine kinase, the protein kinase C (PKC) that can phosphorylate and activate other effector proteins in the cells. Additional secondary signaling pathways can be induced by the increased intracellular Ca2+ level and DAG. Via calcium/calmodulin (Ca2+/CAM)-dependent enzyme, nitric oxide (NO) activity is stimulated to produce an elevated NO level, which results in the activation.
Human H2 receptor protein contains 359 amino-acid residues, and its ligand binding site appears to be similar to the corresponding region of H1R. The most notable difference between the two receptors is the comparatively much shorter third intracellular loop and the longer C-terminus in the H2 receptor sequence. Histamine H2 receptors couple to adenyl cyclase via the Gs protein, and histamine stimulates cAMP production in many different cell types, e.g., the CNS and CNS-derived cells, gastric mucosa, cardiac myocytes, fat cells, vascular smooth cells, basophils and neutrophils. Elevated cAMP concentration activates protein kinase A (PKA), which is the downstream effector kinase of this pathway, phosphorylating a wide variety of proteins in the cells mentioned above. However, the H2R signaling pathway shows a dual face. In addition to the adenyl cyclase-mediated one, histamine through H2 receptor can increase the intracellular Ca2+ ion level in some cell types, e.g., gastric parietal cells and HL-60 leukaemic cell line. This action of histamine seems to be a direct effect mediated by another Gq member of the PTX-sensitive Gprotein family. In contrast to other receptors that stimulate the dual signaling pathway, H2 receptor activates each pathway directly and the required histamine concentration for the stimulation of both systems is identical.
H3 receptor was initially identified on a pharmacological basis. The first report of the H3 receptor came from Arrang et al. who found a new histamine receptor that acted as an autoreceptor which mediated histamine release from neurons. They identified a sequence that encoded a 445-amino acid coding region with low homology to other biogenic amine receptors, which may have allowed it to elude discovery for so long. However, it did have an aspartic acid residue in transmembrane domain 3 which is a conserved residue for receptors that bind to primary amines. The H3 receptor binds to histamine with a high affinity (Kd ~5 nM), which is consistent with its role as an autoreceptor. Most agonists of the receptor are imidazole derivatives related to histamine. Much more work has been done in developing H3 receptor antagonists, since they appear to have more therapeutic utility. The early antagonists were also imidazoles like the agonists. There had been some studies indicating that the receptor is coupled to Gi/o Gproteins. The receptor can also signal via increases in intracellular calcium. Furthermore, it has been shown that activation of rat H3 receptor can increase p44/p42 MAP kinase phosphorylation and arachidonic acid release in transfected cells. As for the cAMP response, both of these responses are PTX-sensitive. Finally, there is some evidence in transfected systems that the H3 receptor can inhibit the activity of Na+/H+ exchangers. One interesting aspect of H3 receptor signaling is that it appears to possess a high degree of constitutive activity; that is, activity in the absence of agonists. This opens up the possibility that H3 receptor ligands that were initially characterized as antagonists may in fact be inverse agonists, i.e., they inhibit the constitutive activity of the receptor.
The primary amino acid sequence of the H4 receptor clearly identifies it as a member of the GPCR family. The 390 amino acid protein is predicted to have seven transmembrane regions, DRY sequence at the end of transmembrane helix 3 and an aspartic acid residue in the second transmembrane domain, which indicate that it is a member of the biogenic amine GPCR family. The aspartic acid residue at position 94 in transmembrane helix 3, which is conserved among the other histamine receptors, is crucial for the binding of histamine. In primary cells, H4 receptor signaling is mediated by increases in intracellular calcium levels. Raible et al. showed that histamine can induce calcium mobilization in human eosinophils and that this effect is not mediated by H1,H2, or H3 receptors, implying a role for the H4 receptor. In mouse primary mast cells, histamine induces calcium mobilization from intracellular stores which can be blocked by H4 receptor antagonists but not by antagonists for other histamine receptors. Thus, in primary cells, activation of H4R leads to increases in intracellular calcium, which in mast cells is mediated by Gi/o proteins and phospholipase C.