Experimental pancreatitis is mediated by low-affinity cholecystokinin receptors that inhibit digestive enzyme secretion.

Abstract

Rats infused with a supramaximally stimulating dose of the cholecystokinin (CCK) analog caerulein develop acute edematous pancreatitis. Using CCK-JMV-180, a recently developed CCK analog that acts as an agonist at high-affinity CCK receptors but antagonizes the effect of CCK at low-affinity receptors, we have determined that caerulein induces pancreatitis by interacting with low-affMnity CCK receptors. Those low-affinity receptors mediate CCK-induced inhibition of digestive enzyme secretion from the pancreas. Our observations, therefore, suggest that this form of experimental pancreatitis results from the inhibition of pancreatic digestive enzyme secretion.

A plasma protease which is expressed during supramaximal stimulation causes in vitro subcellular redistribution of lysosomal enzymes in rat exocrine pancreas.

“…It is clear, however, that inhibition of secretion is not, by itself, sufficient to cause redistribution of cathepsin B because digestive enzyme secretion is inhibited by a supramaximally stimulating concentration of caerulein even in the absence of the plasma factor(s). Similarly, interaction of an agonist such as caerulein with low-affinity receptors, a phenomenon recently noted to play a role in secretagogue-induced pancreatitis (19), cannot by itself be the cause of redistribution because low-affinity receptor occupancy by caerulein occurs even in the absence of the plasma factor(s).…”

Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis

“…It begins when caerulein binds to low-affinity CCK receptors that mediate inhibition of digestive enzyme secretion (18). The earliest changes, each noted to occur within the initial 30 minutes after the start of caerulein administration, include (a) the colocalization of lysosomal hydrolases with digestive enzyme zymogens in cytoplasmic vacuoles (a phenomenon that can be monitored by demonstrating lysosomal hydrolase redistribution from the lysosomeenriched to the zymogen granule-enriched subcellular fraction) (13); (b) intra-acinar cell activation of trypsinogen; and (c) activation of NF-κB.…”

Exocrine specific expression of Connexin32 is dependent on the basic helix-loop-helix transcription factor Mist1

“…Binding of CCK to G-protein coupled receptors initiates a signaling cascade that culminates in the release of intracellular calcium, which in turn promotes movement of the zymogen granules (ZG) toward the apical cell surface and exocytosis of enzymes into pancreatic ducts (Joseph, 1996;McNiven and Marlowe, 1999). Improper signaling leads to impaired exocytosis and premature enzyme activation (Saluja et al, 1989). Owing to this specialized function, acinar cells exhibit extensive extra-and intracellular organization, with the granules aligned to the apical border adjacent to a centrally located duct while the receptors for secretagogue binding are located on the basal aspect of the cell.…”