Cholecystokinin (CCK) Regulation of Pancreatic Acinar Cells: Physiological Actions and Signal Transduction Mechanisms

Abstract

Pancreatic acinar cells synthesize and secrete about 20 digestive enzymes and ancillary proteins with the processes that match the supply of these enzymes to their need in digestion being regulated by a number of hormones (CCK, secretin and insulin), neurotransmitters (acetylcholine and VIP) and growth factors (EGF and IGF). Of these regulators, one of the most important and best studied is the gastrointestinal hormone, cholecystokinin (CCK). Furthermore, the acinar cell has become a model for seven transmembrane, heterotrimeric G protein coupled receptors to regulate multiple processes by distinct signal transduction cascades. In this review, we briefly describe the chemistry and physiology of CCK and then consider the major physiological effects of CCK on pancreatic acinar cells. The majority of the review is devoted to the physiologic signaling pathways activated by CCK receptors and heterotrimeric G proteins and the functions they affect. The pathways covered include the traditional second messenger pathways PLC‐IP3‐Ca 2+ , DAG‐PKC, and AC‐cAMP‐PKA/EPAC that primarily relate to secretion. Then there are the protein‐protein interaction pathways Akt‐mTOR‐S6K, the three major MAPK pathways (ERK, JNK, and p38 MAPK), and Ca 2+ ‐calcineurin‐NFAT pathways that primarily regulate non‐secretory processes including biosynthesis and growth, and several miscellaneous pathways that include the Rho family small G proteins, PKD, FAK, and Src that may regulate both secretory and nonsecretory processes but are not as well understood. © 2019 American Physiological Society. Compr Physiol 9:535‐564, 2019.

NADPH oxidase 1 mediates caerulein-induced pancreatic fibrosis in chronic pancreatitis

“…A number of intracellular pathways have been activated following Nox1-derived ROS, including JNK, p38 MAP kinase, AKT, and ERK1/2 [44]. The same pathways are activated by CCK [45]. We found that caerulein-induced CP caused phosphorylation of AKT and decreased phosphorylation of JNK in WT mice.…”

Experimental Acute Pancreatitis Models: History, Current Status, and Role in Translational Research

“…CCK-8 and CCK-58 have the same effect on Ca 2+ signaling, zymogen activation, and cell death in PACs at high and low agonist concentrations in vitro (Criddle et al, 2009). A recent review has summarized the regulation of the CCK pathway in PACs in detail (Williams, 2019).…”

“…Subsequent studies carried out in animal models that simulate the human disease suggested that the PACs were the initial site of morphological damage (Lerch et al, 1992). The latest reviews summarizes the effects of CCK on PACs (Williams, 2019) and early acinar events in the pathogenesis of AP (Saluja et al, 2019). The most notable limitation of primary PACs is their in vitro viability is relatively short and thus they cannot be used for long-term experiments or subculturing, an advantage that acinar carcinoma cell lines can offer.…”

NanoLuc Bioluminescence-Driven Photodynamic Activation of Cholecystokinin 1 Receptor with Genetically-Encoded Protein Photosensitizer MiniSOG

“…Owing to the wide distribution and participation in important physiological functions, CCK1R and coupled signaling pathways are rather well characterized [27], including coupling to calcium signaling [1,2,28]. In contrast to reversible activation by agonists, one strikingly conspicuous feature of CCK1 receptor pharmacology is that CCK1R such as those present at the basal plasma membrane in rat pancreatic acini are permanently activated by the lowest lying excited state of molecular oxygen, the delta singlet oxygen ( 1 O 2 ) [29][30][31][32].…”