Physiological roles and gene expressions of CCK receptors in the regulation of bile-pancreatic secretion and gastric functions

成年OLETF大鼠的胰腺大小显著小于成年LETO大鼠;然而，CCK-A受体（-/-）小鼠与野生型小鼠之间没有差异。这一发现表明CCK-A受体对大鼠胰腺的自然生长比小鼠胰腺的自然生长更重要。在大鼠中，通过给予促胰液素产生胰腺碳酸氢盐分泌，而促胰液素未能增加小鼠中碳酸氢盐分泌，并且CCK通过CCK-A受体增加小鼠中碳酸氢盐分泌。口服胰蛋白酶抑制剂在5天内增加大鼠胰腺大小，而小鼠需要14天。最近，我们在CCK-A受体基因启动子区发现了两个序列变化，一个是-128位核苷酸的G到T的变化，一个是-81位核苷酸的A到G的变化。各多态性频率均大于1%，且纯合子（T/T，G/G）与等位基因频率显著相关。 ...更多信息 与其他基因型相比，高脂血症患者的体脂百分比明显更高，血清胰岛素和瘦素水平也更高。因此，CCK-A受体启动子区的多态性被认为是与肥胖受试者的体重控制困难相关的单核苷酸多态性（SNP）之一，也与生活方式以及饮食习惯等其他因素相关。近年来，我们发现CCK-A受体启动子区基因多态性与慢性胰腺炎和胆囊结石患者的疾病进程相关。使用荧光素酶报告基因分析，我们调查是否在CCK-A受体基因的多态性启动子序列影响CCK-受体启动子活性。我们发现，主要的多态性构建体，pGL-315/+112（GA），以及其他两个构建体，在瞬时转染实验中表现出几乎相同的活性。多态性-128 G也在CpG二核苷酸序列中。如果在人CCK-A受体的表达中也发现了大鼠CCK-A受体表达中所显示的甲基化效应，则可以揭示该多态性对该基因的转录具有某种影响。在最近的一项研究中，我们证明了启动子区域甲基化的减少与CCK-AR基因的大量表达有关。少

The pancreatic size in adult OLETF rats was significantly lower than that in adult LETO rats ; however, there were no differences between CCK-A receptor(-/-) mice and wild-type mice. This finding indicates that the CCK-A receptor is more important for pancreatic natural growth in rats than it is in mice. Pancreatic bicarbonate secretion was produced by the administration of secretin in rats, whereas secretin failed to increase bicarbonate secretion in mice, and CCK increased bicarbonate secretion via CCK-A receptor in mice. Oral administration of trypsin inhibitor increased pancreatic size in rats within 5 days, whereas 14 days were required in mice. Lack of CCK-BR enhanced gastric emptying of a liquid load.Recently, we identified two sequence changes, a G to T change in nucleotide -128, and an A to G change in nucleotide -81, in the promoter region of the CCK-A receptor gene. The frequency of each polymorphism was more than 1%, and the homozygote (T/T, G/G) is associated with a signif … More icantly higher percent body fat and higher levels of serum insulin and leptin than are the other genotypes. Therefore, the CCK-A receptor polymorphism in the promoter region is considered to be one of single nucleotide polymorphisms (SNPs) related to weight control difficulties in obese subjects, and also to other factors such as lifestyle as well as eating habits. Recently, we found that this CCK-A receptor promoter polymorphism was corresponded to the disease process in chronic pancreatitis and gallstone patients. Using a luciferase reporter assay, we investigated whether or not the polymorphic promoter sequence in the CCK-A receptor gene affected CCK- receptor promoter activity. We found that the major polymorphic construct, pGL-315/+112 (GA), as well as the other two constructs, showed almost the same activity in transient transfection experiments. The polymorphic -128 G is also in the CpG dinucleotide sequence. If an effect of methylation, as shown in the case of rat CCK-A receptor expression, is also found in the case of human CCK-A receptor expression, this polymorphism may be revealed to have some effect on the transcription of this gene. In a recent study, we demonstrated that reduced methylation in the promoter region was related to the substantial expression of the CCK-AR gene. Less