Cholecystokinin Activates a Variety of Intracellular Signal Transduction Mechanisms in Rodent Pancreatic Acinar Cells

Abstract

Cholecystokinin (CCK) acting through its G protein-coupled receptor is now known to activate a variety of intracellular signaling mechanisms and thereby regulate a complex array of cellular functions in pancreatic acinar cells. The best studied mechanism is the coupling through heterotrimeric G proteins of the G q family to activate a phospholipase C leading to an increase in inositol trisphosphate and release of intracellular Ca 2π . This pathway along with protein kinase C activation in response to the increase in diacylglycerol stimulates the secretion of digestive enzymes by the process of exocytosis. CCK also activates signaling pathways in acini more related to other processes. The three mitogen activated protein kinase cascades leading to ERKs, JNKs and p38 MAPK are all activated by CCK. CCK activates the ERK cascade by PKC activation of Raf which in turn activates MEK and ERKs. JNKs are activated by a distinct mechanism whish requires higher concentrations of CCK. Both ERKs and JNKs are presumed to regulate gene expression. CCK activation of p38 MAPK also plays a role in regulating the actin cytoskeleton through phosphorylation of the small heat shock protein HSP27. The PI3K-PKB-mTOR pathway is activated by CCK and plays a major role in regulating protein synthesis at the translational level. This includes both activation of p70 S6K leading to phosphorylation of ribosomal protein S6 and the phosphorylation of the binding protein for initiation factor 4E leading to formation of the mRNA cap binding complex. Other signaling pathways activated by CCK receptors include NF-kB and a variety of tyrosine kinases. Further work is needed to understand how CCK receptors activate most of the above pathways and to better understand the biological events regulated by these diverse signaling pathways.

Cholecystokinin-8S-Induced Intracellular Calcium Signaling in Acutely Isolated Periaqueductal Gray Neurons of the Rat

“…25) These results suggest that CCK is a main neurotransmitter to modulate neuronal activities in the PAG and also indicate possible CCK-mediated modulation on intracellular Ca 2ϩ signaling via Ga q /PLC pathways in the CNS as has occurred in pancreatic cells [19][20][21] and several cell lines. [22][23][24] In the present study, we examined the effects of CCK on [Ca 2ϩ ] i in acutely dissociated PAG neurons using a sulfated form of CCK octapeptide (CCK-8S), the most abundant and endogenously active form of CCK in the brain.…”

“…8,9) Both CCK receptors belong to a superfamily of G protein-coupled receptors (GPCR). 7,17,18) Direct coupling of CCK 1 and CCK 2 receptors onto Ga q to activate phospholipase C (PLC) and cause intracellular Ca 2ϩ signaling has been well demonstrated in pancreatic acinar cells [19][20][21] and several cell lines. [22][23][24] However, this effect is not clearly demonstrated in the central nervous system (CNS).…”

Stabilization of Exocytosis by Dynamic F-actin Coating of Zymogen Granules in Pancreatic Acini

“…Our data further demonstrated that the increases in [Ca 2ϩ ] i were not sufficient for vacuole formation since large and sustained increases in [Ca 2ϩ ] i caused by photolysis of the caged-Ca 2ϩ compound did not induce vacuole formation. CCK receptors are known to activate signaling cascades other than Ca 2ϩ signaling (42). Such disruption of Factin coating may account for the diffuse staining of F-actin detected previously in the pancreas of animal models of acute pancreatitis by one-photon confocal microscopy (16,43).…”

Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini

“…Active IRE1 binds and clusters TNF receptor-associating factor 2, an adaptor protein that phosphorylates c-Jun NH 2 -terminal kinase (JNK). JNK, known to be phosphorylated in pancreatitis, activates downstream transcription factors, such as c-jun, c-fos, and Sap-1 or regulates RNA stability (51,57).…”