Molecular mechanisms in therapy of acid-related diseases

Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists. Received 30 May 2007; received after revision 15 August 2007; accepted 13 September 2007     

Role of the ubiquitin–proteasome system in the regulation of P2Y13 receptor expression: impact on hepatic HDL uptake

The protective effect of high density lipoproteins (HDL) against atherosclerosis is mainly attributed to their capacity to transport excess cholesterol from peripheral tissues back to the liver for further elimination into the bile, a process called reverse cholesterol transport (RCT). Recently, the importance of the P2Y₁₃ receptor (P2Y₁₃-R) was highlighted in HDL metabolism since HDL uptake by the liver was decreased in P2Y₁₃-R deficient mice, which translated into impaired RCT. Here, we investigated for the first time the molecular mechanisms regulating cell surface expression of P2Y₁₃-R. When transiently expressed, P2Y₁₃-R was mainly detected in the endoplasmic reticulum (ER) and strongly subjected to proteasome degradation while its homologous P2Y₁₂ receptor (P2Y₁₂-R) was efficiently targeted to the plasma membrane. We observed an inverse correlation between cell surface expression and ubiquitination level of P2Y₁₃-R in the ER, suggesting a close link between ubiquitination of P2Y₁₃-R and its efficient targeting to the plasma membrane. The C-terminus tail exchange between P2Y₁₃-R and P2Y₁₂-R strongly restored plasma membrane expression of P2Y₁₃-R, suggesting the involvement of the intra-cytoplasmic tail of P2Y₁₃-R in expression defect. Accordingly, proteasomal inhibition increased plasma membrane expression of functionally active P2Y₁₃-R in hepatocytes, and consequently stimulated P2Y₁₃-R-mediated HDL endocytosis. Importantly, proteasomal inhibition strongly potentiated HDL hepatic uptake (>200 %) in wild-type but not in P2Y₁₃-R-deficient mice, thus reinforcing the role of P2Y₁₃-R expression in regulating HDL metabolism. Therefore, specific inhibition of the ubiquitin–proteasome system might be a novel powerful HDL therapy to enhance P2Y₁₃-R expression and consequently promote the overall RCT.     

Postnatal changes in phosphatase and non-specific esterase activity in the large intestine of the rat

Zusammenfassung Phosphatasen- und Esterasenaktivität in Enterozyten des Rattendickdarms ändert sich während der postnatalen Entwicklung. Alkalische und saure Phosphatase ist bei neugeborenen und jungen Ratten im oralen Dickdarmabschnitt stark positiv. Die Annahme der Beteiligung des Dickdarmes an Resorption und Metabolismus wird vorausgesetzt.     

Bicuculline and picrotoxin block γ-aminobutryic acid-gated Cl− conductance by different mechanisms

Summary Using isolated, internally perfused bullfrog dorsal root ganglion cells we have studied the dose-response curves for -aminobutyric acid (GABA) in the presence of internally or externally applied GABA antagonists. With external application of antagonists the inhibition of the GABA current by bicuculline was competitive and that by picrotoxin was noncompetitive. Picrotoxin but not bicuculline blocked when internally perfused.To whom reprint requests should be addressed.Acknowledgments. We thank Drs S. Minakami and S. Yasui for helpful discussions and comments.     

Effect of pylorus ligation on gastric mucosal mast cell population in normal and adrenalectomised albino rats

Summary Pylorus ligation in normal albino rats acts like a stressor leading to degranulation of mast cells in gastric mucosa, thereby decreasing their number. This decrease is less pronounced when pylorus ligation is done in adrenalectomized rats. This implies that action of a stressor on gastric function involves the adrenal steroids which liberate the powerful gastric stimulant histamine from gastric mucosal mast cells.     

Development of the new Pacinian corpuscles. Studies on the foreign innervation of mesentery

Zusammenfassung Nach Implantation des proximalen Stumpfes eines afferenten, somatosensiblen Nerven in das Mesenterium einer Katze bilden sich um die auswachsenden Nervenfasern nach 3–5 Monaten neue, aber dem Ort entsprechende Rezeptoren aus, im Fall des Katzenmesenteriums also Pacinische Körperchen, Rezeptoren, die normalerweise nicht im Gebiet des implantierten Nerven vorkommen.     

Bicuculline and picrotoxin block gamma-aminobutyric acid-gated Cl- conductance by different mechanisms

Using isolated, internally perfused bullfrog dorsal root ganglion cells we have studied the dose-response curves for gamma-aminobutyric acid (GABA) in the presence of internally or externally applied GABA antagonists. With external application of antagonists the inhibition of the GABA current by bicuculline was competitive and that by picrotoxin was noncompetitive. Picrotoxin but not bicuculline blocked when internally perfused.