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

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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