Pathways

Histamine is a biogenic amine synthesized from L-histidine exclusively by L-histidine decarboxylase, which uses pyridoxal-5’-phosphate as a cofactor. Histidine decarboxylase is widely expressed throughout various cells in the body, such as gastric mucosa, neurons, parietal cells, mast cells, and basophils. Modulation of histamine’s effect occurs through four types of receptors: H1, H2, H3, and H4. Histamine receptors are G-protein coupled receptors, which are 7-transmembrane chain proteins that mediate the effect of several molecules. H1 receptors are Gq coupled receptors. Its downstream effects are mediated by increased activity of phospholipase C, increased cytoplasmic calcium, and a subsequent increase in protein kinase C activity.[8] H2 receptors are Gs-coupled receptors. Its downstream effects are mediated by an increase in intracellular cAMP and activation of protein kinase A.[5] Both H3 and H4 receptors are G protein-coupled receptors. A decrease in intracytoplasmic cAMP mediates the downstream effects of histamine. H2RAs decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and activity of the endogenous ligand histamine. H2 blockers thus function as competitive antagonists. Normally, after a meal, gastrin stimulates histamine release from enterochromaffin-like cells, which then binds to histamine H2 receptors on gastric parietal cells and leads to gastric acid release. This increase in gastric acid release occurs through the activation of adenylate cyclase, which raises intracellular cAMP levels. cAMP then activates protein kinase A (PKA), which, among other functions, phosphorylates proteins involved in the movement of H+/K+ ATPase transporters to the plasma membrane. The increase of H+/K+ ATPase transporters at the plasma membrane allows for the secretion of more acid from parietal cells. By blocking the histamine receptor and thus histamine stimulation of parietal cell acid secretion, H2RAs suppress both stimulated and basal gastric acid secretion induced by histamine. Antagonists of histamine H2 receptor antagonist are used to treat gastroesophageal reflux disease and various ulcers. They display more selectivity towards H2 histamine receptors compared to other H1 anti-histamines. After being taken orally, They are absorbed in the GI tract and travel through the blood to get to the stomach epithelium. They block the downstream Gs cascade which produces cyclic adenosine monophosphate (cAMP) which is an activator for the potassium-hydrogen ATPase pump (H+/K+ ATPase pump). The pump is responsible for secreting hydrogen ions into the stomach lumen increasing the acidity of the stomach environment. By blocking adenylate cyclase signalling pathway from the histamine H2 receptor less hydrogen ions are secreted into the stomach lumen increasing the pH. The less acidic environment doesn't irritate the stomach as much. The H+/K+ ATPase pump can still be activated through gastrin and acetylcholine through the phospholipase C signalling pathway, but blocking the adenylate cyclase pathway helps reduce the acidity.

Histamine is a biogenic amine synthesized from L-histidine exclusively by L-histidine decarboxylase, which uses pyridoxal-5’-phosphate as a cofactor. Histidine decarboxylase is widely expressed throughout various cells in the body, such as gastric mucosa, neurons, parietal cells, mast cells, and basophils. Modulation of histamine’s effect occurs through four types of receptors: H1, H2, H3, and H4. Histamine receptors are G-protein coupled receptors, which are 7-transmembrane chain proteins that mediate the effect of several molecules. H1 receptors are Gq coupled receptors. Its downstream effects are mediated by increased activity of phospholipase C, increased cytoplasmic calcium, and a subsequent increase in protein kinase C activity.[8] H2 receptors are Gs-coupled receptors. Its downstream effects are mediated by an increase in intracellular cAMP and activation of protein kinase A.[5] Both H3 and H4 receptors are G protein-coupled receptors. A decrease in intracytoplasmic cAMP mediates the downstream effects of histamine. H2RAs decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and activity of the endogenous ligand histamine. H2 blockers thus function as competitive antagonists. Normally, after a meal, gastrin stimulates histamine release from enterochromaffin-like cells, which then binds to histamine H2 receptors on gastric parietal cells and leads to gastric acid release. This increase in gastric acid release occurs through the activation of adenylate cyclase, which raises intracellular cAMP levels. cAMP then activates protein kinase A (PKA), which, among other functions, phosphorylates proteins involved in the movement of H+/K+ ATPase transporters to the plasma membrane. The increase of H+/K+ ATPase transporters at the plasma membrane allows for the secretion of more acid from parietal cells. By blocking the histamine receptor and thus histamine stimulation of parietal cell acid secretion, H2RAs suppress both stimulated and basal gastric acid secretion induced by histamine. Antagonists of histamine H2 receptor antagonist are used to treat gastroesophageal reflux disease and various ulcers. They display more selectivity towards H2 histamine receptors compared to other H1 anti-histamines. After being taken orally, They are absorbed in the GI tract and travel through the blood to get to the stomach epithelium. They block the downstream Gs cascade which produces cyclic adenosine monophosphate (cAMP) which is an activator for the potassium-hydrogen ATPase pump (H+/K+ ATPase pump). The pump is responsible for secreting hydrogen ions into the stomach lumen increasing the acidity of the stomach environment. By blocking adenylate cyclase signalling pathway from the histamine H2 receptor less hydrogen ions are secreted into the stomach lumen increasing the pH. The less acidic environment doesn't irritate the stomach as much. The H+/K+ ATPase pump can still be activated through gastrin and acetylcholine through the phospholipase C signalling pathway, but blocking the adenylate cyclase pathway helps reduce the acidity.

Histamine is a biogenic amine synthesized from L-histidine exclusively by L-histidine decarboxylase, which uses pyridoxal-5’-phosphate as a cofactor. Histidine decarboxylase is widely expressed throughout various cells in the body, such as gastric mucosa, neurons, parietal cells, mast cells, and basophils. Modulation of histamine’s effect occurs through four types of receptors: H1, H2, H3, and H4. Histamine receptors are G-protein coupled receptors, which are 7-transmembrane chain proteins that mediate the effect of several molecules. H1 receptors are Gq coupled receptors. Its downstream effects are mediated by increased activity of phospholipase C, increased cytoplasmic calcium, and a subsequent increase in protein kinase C activity.[8] H2 receptors are Gs-coupled receptors. Its downstream effects are mediated by an increase in intracellular cAMP and activation of protein kinase A.[5] Both H3 and H4 receptors are G protein-coupled receptors. A decrease in intracytoplasmic cAMP mediates the downstream effects of histamine. H2RAs decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and activity of the endogenous ligand histamine. H2 blockers thus function as competitive antagonists. Normally, after a meal, gastrin stimulates histamine release from enterochromaffin-like cells, which then binds to histamine H2 receptors on gastric parietal cells and leads to gastric acid release. This increase in gastric acid release occurs through the activation of adenylate cyclase, which raises intracellular cAMP levels. cAMP then activates protein kinase A (PKA), which, among other functions, phosphorylates proteins involved in the movement of H+/K+ ATPase transporters to the plasma membrane. The increase of H+/K+ ATPase transporters at the plasma membrane allows for the secretion of more acid from parietal cells. By blocking the histamine receptor and thus histamine stimulation of parietal cell acid secretion, H2RAs suppress both stimulated and basal gastric acid secretion induced by histamine. Antagonists of histamine H2 receptor antagonist are used to treat gastroesophageal reflux disease and various ulcers. They display more selectivity towards H2 histamine receptors compared to other H1 anti-histamines. After being taken orally, They are absorbed in the GI tract and travel through the blood to get to the stomach epithelium. They block the downstream Gs cascade which produces cyclic adenosine monophosphate (cAMP) which is an activator for the potassium-hydrogen ATPase pump (H+/K+ ATPase pump). The pump is responsible for secreting hydrogen ions into the stomach lumen increasing the acidity of the stomach environment. By blocking adenylate cyclase signalling pathway from the histamine H2 receptor less hydrogen ions are secreted into the stomach lumen increasing the pH. The less acidic environment doesn't irritate the stomach as much. The H+/K+ ATPase pump can still be activated through gastrin and acetylcholine through the phospholipase C signalling pathway, but blocking the adenylate cyclase pathway helps reduce the acidity.

Histamine is a biogenic amine synthesized from L-histidine exclusively by L-histidine decarboxylase, which uses pyridoxal-5’-phosphate as a cofactor. Histidine decarboxylase is widely expressed throughout various cells in the body, such as gastric mucosa, neurons, parietal cells, mast cells, and basophils. Modulation of histamine’s effect occurs through four types of receptors: H1, H2, H3, and H4. Histamine receptors are G-protein coupled receptors, which are 7-transmembrane chain proteins that mediate the effect of several molecules. H1 receptors are Gq coupled receptors. Its downstream effects are mediated by increased activity of phospholipase C, increased cytoplasmic calcium, and a subsequent increase in protein kinase C activity.[8] H2 receptors are Gs-coupled receptors. Its downstream effects are mediated by an increase in intracellular cAMP and activation of protein kinase A.[5] Both H3 and H4 receptors are G protein-coupled receptors. A decrease in intracytoplasmic cAMP mediates the downstream effects of histamine. H2RAs decrease gastric acid secretion by reversibly binding to histamine H2 receptors located on gastric parietal cells, thereby inhibiting the binding and activity of the endogenous ligand histamine. H2 blockers thus function as competitive antagonists. Normally, after a meal, gastrin stimulates histamine release from enterochromaffin-like cells, which then binds to histamine H2 receptors on gastric parietal cells and leads to gastric acid release. This increase in gastric acid release occurs through the activation of adenylate cyclase, which raises intracellular cAMP levels. cAMP then activates protein kinase A (PKA), which, among other functions, phosphorylates proteins involved in the movement of H+/K+ ATPase transporters to the plasma membrane. The increase of H+/K+ ATPase transporters at the plasma membrane allows for the secretion of more acid from parietal cells. By blocking the histamine receptor and thus histamine stimulation of parietal cell acid secretion, H2RAs suppress both stimulated and basal gastric acid secretion induced by histamine. Antagonists of histamine H2 receptor antagonist are used to treat gastroesophageal reflux disease and various ulcers. They display more selectivity towards H2 histamine receptors compared to other H1 anti-histamines. After being taken orally, They are absorbed in the GI tract and travel through the blood to get to the stomach epithelium. They block the downstream Gs cascade which produces cyclic adenosine monophosphate (cAMP) which is an activator for the potassium-hydrogen ATPase pump (H+/K+ ATPase pump). The pump is responsible for secreting hydrogen ions into the stomach lumen increasing the acidity of the stomach environment. By blocking adenylate cyclase signalling pathway from the histamine H2 receptor less hydrogen ions are secreted into the stomach lumen increasing the pH. The less acidic environment doesn't irritate the stomach as much. The H+/K+ ATPase pump can still be activated through gastrin and acetylcholine through the phospholipase C signalling pathway, but blocking the adenylate cyclase pathway helps reduce the acidity.

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.

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.