Williams John A, Sans M Dolors, Tashiro Mitsuo, Schäfer Claus, Bragado M Julia, Dabrowski Andrzej
Department of Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Pharmacol Toxicol. 2002 Dec;91(6):297-303. doi: 10.1034/j.1600-0773.2002.910606.x.
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 Gq family to activate a phospholipase C leading to an increase in inositol trisphosphate and release of intracellular Ca2+. 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 which 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-kappaB 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.
现已明确，胆囊收缩素（CCK）通过其G蛋白偶联受体发挥作用，可激活多种细胞内信号传导机制，从而调节胰腺腺泡细胞中一系列复杂的细胞功能。研究最为深入的机制是通过Gq家族的异源三聚体G蛋白进行偶联，激活磷脂酶C，导致三磷酸肌醇增加并释放细胞内Ca2+。该途径与二酰基甘油增加后蛋白激酶C的激活一起，通过胞吐作用刺激消化酶的分泌。CCK还激活腺泡中与其他过程更相关的信号通路。导致细胞外信号调节激酶（ERK）、c-Jun氨基末端激酶（JNK）和p38丝裂原活化蛋白激酶（MAPK）的三种丝裂原活化蛋白激酶级联反应均由CCK激活。CCK通过PKC激活Raf来激活ERK级联反应，Raf进而激活MEK和ERK。JNK通过一种独特的机制被激活，这需要更高浓度的CCK。ERK和JNK都被认为可调节基因表达。CCK激活p38 MAPK在通过小热休克蛋白HSP27的磷酸化调节肌动蛋白细胞骨架方面也发挥作用。PI3K-PKB-mTOR途径被CCK激活，并在翻译水平调节蛋白质合成中起主要作用。这包括激活p70 S6K导致核糖体蛋白S6的磷酸化，以及起始因子4E结合蛋白的磷酸化导致mRNA帽结合复合物的形成。CCK受体激活的其他信号通路包括核因子κB和多种酪氨酸激酶。需要进一步开展工作，以了解CCK受体如何激活上述大多数途径，并更好地理解这些不同信号通路所调节的生物学事件。
