Molecular cloning of cholecystokinin (CCK) and CCK-A receptor and mechanism of CCK-induced gastrointestinal motility in Suncus murinus
Molecular cloning of cholecystokinin (CCK) and CCK-A receptor and mechanism of CCK-induced gastrointestinal motility in Suncus murinus
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DOI：
10.1016/j.ygcen.2022.114074
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发表时间：
2022-10-01
影响因子：
2.7
通讯作者：
Sakata, Ichiro
中科院分区：
文献类型：
--
作者：
Takemi, Shota;Honda, Wataru;Sakata, Ichiro
胆囊收缩素（Cholecystokinin，CCK）是一种主要由小肠内分泌I细胞分泌的肽类激素，其功能是调节胆囊收缩、胃排空、胃肠（GI）运动和饱腹感。CCK在这些外周组织中的细胞效应主要通过CCK-A受体介导，CCK-A受体存在于人和动物模型的平滑肌、肠神经元和迷走传入神经元中。尽管已经报道CCK的各种功能是神经介导的，但它也可以通过平滑肌上的CCK受体刺激收缩。然而，胆囊收缩素诱导胃肠道收缩的神经和细胞机制尚不清楚。本研究首先测定了家麝鼩（Suncus murinus，实验室品系）CCK和CCK-A受体沿着的cDNA和氨基酸序列，以及CCK mRNA和CCK产生细胞的分布，探讨了CCK诱导胃肠道收缩的机制。结果表明，成熟的向日葵CCK-8与其它哺乳动物的CCK-8完全相同，向日葵CCK-A受体与人、狗、小鼠和大鼠的CCK-A受体的核苷酸和氨基酸序列高度同源。在小肠和结肠中发现了主要的CCK mRNA和CCK产生细胞。在器官浴实验中，CCK-8可引起胃、十二指肠和空肠的剂量依赖性收缩，这些收缩可被阿托品和CCK-A受体拮抗剂抑制。这些结果表明，CCK-8诱导的收缩是介导的肌间胆碱能神经网络和CCK-A受体是部分负责CCK-8诱导的收缩。本研究表明，悬雍垂是研究CCK参与胃肠运动的一种有用的动物模型。
Cholecystokinin (CCK) is a peptide hormone mainly secreted by small intestinal endocrine I-cells and functions as a regulator of gallbladder contraction, gastric emptying, gastrointestinal (GI) motility, and satiety. The cellular effects of CCK in these peripheral tissues are predominantly mediated via CCK-A receptors which are found in smooth muscles, enteric neurons, and vagal afferent neurons in humans and animal models. Although various functions of CCK have been reported to be neurally mediated, it can also stimulate contraction via the CCK receptor on the smooth muscle. However, the entire underlying neural and cellular mechanisms involved in CCKinduced GI contractions are not clearly understood. Here, we first determined the cDNA and amino acid sequences of CCK and CCK-A receptor along with the distributions of cck mRNA and CCK-producing cells in house musk shrew (Suncus murinus, the laboratory strain named as suncus) and examined the mechanism of CCKinduced contraction in the GI tract. Mature suncus CCK-8 was identical to other mammalian species tested here, and suncus CCK-A receptor presented high nucleotide and amino acid homology with that of human, dog, mouse, and rat, respectively. Suncus CCK mRNA and CCK-producing cells were found mainly in small intestine and colon. In the organ bath study, CCK-8 induced dose-dependent contractions in the suncus stomach, duodenum, and jejunum, and these contractions were inhibited by atropine and CCK-A receptor antagonist. These results suggest that CCK-8-induced contraction is mediated in the myenteric cholinergic neural network and that CCK-A receptor is partly responsible for CCK-8-induced contractions. This study indicates that suncus is a useful animal model to study the functions of CCK involved in GI motility.