Role of the Calcium Sensing Receptor in Meal Stimulated Gastrin Secretion

摄入营养物质的分子识别导致胃肠道激素的分泌，调节消化和肠道运动，这是吸收这些营养物质所必需的。氨基酸、短链脂肪酸、碳水化合物和腔内pH值的变化是已知的胃泌素、胆囊收缩素和分泌素的有效刺激物，这些是调节消化、分泌和运动的一些最重要的胃肠激素。据推测，负责这些营养物质化学感觉的细胞分布在胃肠道粘膜层，也可能是肠神经系统内的神经元。这些化学感觉细胞固有的分散性和缺乏任何已知的标记来识别它们，为解决营养物质识别的分子基础带来了难题。钙作用于胃G细胞上的钙感应受体，可刺激胃泌素的分泌。除了二价阳离子外，CaSR已被证明是氨基酸和pH的多模态传感器。因此，我们假设胃窦G细胞上表达的胃钙感应受体（CaSR）是生理上相关的传感器，在体内介导蛋白胨、氨基酸（尤其是芳香氨基酸）和pH刺激胃泌素的释放。

Molecular recognition of ingested nutrients results in the secretion of gastrointestinal hormones regulating digestion and gut motility necessary for absorption of these nutrients. Amino acids, short chain fatty acids, carbohydrates and changes in intraluminal pH are known potent stimulators of gastrin, cholecystokinin and secretin, some of the most important gastrointestinal hormones regulating digestion, secretion and motility. The cells responsible for chemosensation of these nutrients are presumed to be scattered along the mucosal layer lining the gastrointestinal tract and may possibly be neurons within the enteric nervous system. The inherent dispersed nature of these chemosensory cells and the lack of any known markers for their identification create a difficult problem for solving the molecular basis of nutrient recognition. Calcium acting at the calcium sensing receptor on gastric G cells has been shown to stimulate the secretion of gastrin. The CaSR has been shown to be a multimodal sensor for amino aicds and pH in addition to divalent cations. Therefore, we hypothesised that the gastric calcium sensing receptor (CaSR) expressed on antral G cells is the physiologically relevant sensor mediating peptone, amino acids (especially aromatic amino acids) and pH stimulated gastrin release in vivo. This work utilized CaSR and parathyroid hormone (PTH) gene deleted mice provided by Martin R. Pollak (JCI 111:1021-1028, 2003). Plasma gastrin response to peptone, phenylalanine (Phe) and pH was assessed in littermates homozygous deleted (KO) (CaSR- /- /PTH- / -), heterozygous (HET) (CaSR+ /- /PTH- / -) and wild type (WT) (CaSR+ /+/PTH- / -) for the CaSR gene or WT C57/B6 mice. Mice were fasted overnight and either fed ad libitum or gavaged with either peptone (8%), Phe (100 mM), or Hepes (150 mM, pH 7.0) as a bolus or parenteral carbacol (5 mg) or bombesin (50 ug/kg) and the peak gastrin response for each agent was measured by RIA. Gastric acid secretion were measured in response to gastrin -17 (1 mg/kg), histamine (10 mg/kg) or carbachol (5 mg). Hematoxylin and eosin staining and immunohistochemistry was performed on frozen sections from the stomach using rabbit anti-gastrin. We found that CaSR deficient mice do not secrete gastrin in response to intraluminal stimulation with calcium, peptone, L-phenylalanine and elevated pH. However, CaSR deficient mice responded to parenteral bombesin and carbacol similar to WT mice. The gastrin response for ad libitum and gavage feeding in the heterozygous and WT littermates was similar to that observed for WT C57/B6 control mice. High Ca++ dietary correction of plasma Ca++ in the CaSR deficient mice did not restore their gastrin response. CaSR deficient mice expressed a decreased number of antral G cells and gastrin content. They also had an elevated resting gastric pH and reduced basal acid secretion, although they displayed a normal gastric acid secretory response to exogenous gastrin and histamine. From these studies we learned that gastric CaSRs are necessary for the physiological sensing of intraluminal nutrients such as rat chow, peptone, Phe and elevated pH that results in the stimulated release of gastrin from antral G cells. Whether the sensing of these stimulants is directly mediated by CaSRs on gastric antral G cells awaits further studies using isolated G cells. In addition, we found an unexpected role of CaSR in determining antral G cell number.