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Adenylate cyclase type 2 Potassium- transporting ATPase subunit beta Potassium- transporting ATPase alpha chain 1 Muscarinic acetylcholine receptor M3 Gastrin Gastrin/cholecystokinin type B receptor Carbonic anhydrase 1 Histamine H2 receptor Guanine nucleotide- binding protein G(s) subunit alpha isoforms short Gβ Guanine nucleotide- binding protein G(I)/G(S)/G(O) subunit gamma-12 Guanine nucleotide- binding protein G(s) subunit alpha isoforms short Adenylate cyclase type 2 Histamine H2 receptor Guanine nucleotide- binding protein G(s) subunit alpha isoforms short Gβ Guanine nucleotide- binding protein G(I)/G(S)/G(O) subunit gamma-12 Histamine H2 receptor Gβ Guanine nucleotide- binding protein G(I)/G(S)/G(O) subunit gamma-12 Histamine cAMP Acetylcholine Inositol 1,4,5- trisphosphate Histamine GTP GDP Adenosine triphosphate PPi H2O CO2 HCO3- H+ ATP H2O K+ ADP Pi H+ K+ Magnesium Zinc (II) ion GDP GTP Magnesium Histamine GTP Histamine Guanine nucleotide- binding protein G(s) subunit alpha isoforms short Gq Signalling Pathway GTP βzole Stomach Lumen Gastric Parietal Cell Cytosol Basolateral Membrane Apical Membrane Enterochromaffin-like cell Gastric Parietal Cell Stomach Lumen Administered orally as betazole hydrochloride (leading to first-pass metabolism in the liver), betazole circulates in the blood until it reaches the stomach. It can also be administered subcutaneously or intramuscularly (for more rapid action). Betazole is an H2 receptor-specific histamine analogue that binds reversibly to trigger the G-protein signaling cascade. Normally after histamine binds, a Gs protein is activated and activates adenylate cyclase type 2 to form a complex. This GPCR signalling cascade proceeds at an increased rate with betazole. The adenylate cyclase-Gs complex after being activated works to convert adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). More cAMP is formed compared to basal levels with increased histamine and/or betazole activity. cAMP is partially responsible for activating the potassium-hydrogen ATPase transporter which pumps hydrogen ions into the stomach lumen. Higher levels of cAMP increase the activity of this pump so more hydrogen ions are secreted. Hydrogen ions are produced from the conversion of carbon dioxide into bicarbonate. Betazole increases acidity (i.e. it lowers pH). Acetylcholine and gastrin can activate the potassium-hydrogen ATPase pump to maintain acidity of the stomach lumen independent of histamine-related actions. Betazole increases stomach acid levels by acting specifically as a H2 receptor agonist and has no cholingeric, central nervous system, or other off-target effects, making it a useful tool in clinical diagnostics. Enterochromaffin-like cells along the stomach epithelium (especially around the fundus) produce histamine when they are stimulated by gastrin circulating in the blood. These cells release histamine through vesicles to bind to neighbouring parietal cells, which can produce gastric acid upon histamine stimulation. Capillary Interstitial Space Activation
ADCY2 ATP4B ATP4A CHRM3 Unknown CCKBR CA1 HRH2 GNAS GNB1 GNG12 GNAS ADCY2 HRH2 GNAS GNB1 GNG12 HRH2 GNB1 GNG12 Histamine cAMP Acetylcholine Inositol 1,4,5- trisphosphate Histamine Guanosine triphosphate Guanosine diphosphate Adenosine triphosphate Pyrophosphate Water Carbon dioxide Hydrogen carbonate Hydrogen Ion Adenosine triphosphate Water Potassium Adenosine diphosphate Phosphate Hydrogen Ion Potassium Guanosine diphosphate Guanosine triphosphate Histamine Guanosine triphosphate Histamine GNAS Gq Signalling Pathway Guanosine triphosphate βzole
ADCY2 ATP4B ATP4A CHRM3 CCKBR CA1 HRH2 GNAS GNB1 GNG12 GNAS ADCY2 HRH2 GNAS GNB1 GNG12 HRH2 GNB1 GNG12 Hsm cAMP ACh Inotp Hsm GTP GDP ATP PPi H2O CO2 HCO3- H+ ATP H2O K+ ADP Pi H+ K+ Mg2+ Zinc GDP GTP Mg2+ Hsm GTP Hsm GNAS Gq Si P GTP βzole Stomach Lumen Gastric Parietal Cell Cytosol Basolateral Membrane Apical Membrane Enterochromaffin-like cell Gastric Parietal Cell Stomach Lumen Administered orally as betazole hydrochloride (leading to first-pass metabolism in the liver), betazole circulates in the blood until it reaches the stomach. It can also be administered subcutaneously or intramuscularly (for more rapid action). Betazole is an H2 receptor-specific histamine analogue that binds reversibly to trigger the G-protein signaling cascade. Normally after histamine binds, a Gs protein is activated and activates adenylate cyclase type 2 to form a complex. This GPCR signalling cascade proceeds at an increased rate with betazole. The adenylate cyclase-Gs complex after being activated works to convert adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). More cAMP is formed compared to basal levels with increased histamine and/or betazole activity. cAMP is partially responsible for activating the potassium-hydrogen ATPase transporter which pumps hydrogen ions into the stomach lumen. Higher levels of cAMP increase the activity of this pump so more hydrogen ions are secreted. Hydrogen ions are produced from the conversion of carbon dioxide into bicarbonate. Betazole increases acidity (i.e. it lowers pH). Acetylcholine and gastrin can activate the potassium-hydrogen ATPase pump to maintain acidity of the stomach lumen independent of histamine-related actions. Betazole increases stomach acid levels by acting specifically as a H2 receptor agonist and has no cholingeric, central nervous system, or other off-target effects, making it a useful tool in clinical diagnostics. Enterochromaffin-like cells along the stomach epithelium (especially around the fundus) produce histamine when they are stimulated by gastrin circulating in the blood. These cells release histamine through vesicles to bind to neighbouring parietal cells, which can produce gastric acid upon histamine stimulation. Capillary Interstitial Space Activation
ADCY2 ATP4B ATP4A CHRM3 CCKBR CA1 HRH2 GNAS GNB1 GNG12 GNAS ADCY2 HRH2 GNAS GNB1 GNG12 HRH2 GNB1 GNG12 Hsm cAMP ACh Inotp Hsm GTP GDP ATP Ppi H2O CO2 HCO3 H+ ATP H2O K+ ADP Pi H+ K+ GDP GTP Hsm GTP Hsm GNAS Gq Si P GTP βzole