Characterization of the Carboxyl-terminal Domain of the Rat Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor
Characterization of the Carboxyl-terminal Domain of the Rat Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor
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大鼠葡萄糖依赖性促胰岛素多肽 (GIP) 受体羧基末端结构域的表征
DOI：
10.1074/jbc.274.35.24593
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
C. Mcintosh
中科院分区：
文献类型：
--
作者：
M. Wheeler;R. Gelling;S. Hinke;Ba Tu;R. Pederson;F. Lynn;J. Ehses;C. Mcintosh
葡萄糖依赖性促胰岛素多肽（GIP）是一种参与调节胰岛素分泌的胃肠激素。在非胰岛素依赖型糖尿病中，胰岛素对GIP的反应减弱，可能是由于信号转导改变或受体数量减少。定点突变被用来构建截短的GIP受体，以研究羧基末端尾（CT）在结合，信号传导和受体内化中的重要性。在COS-7或CHO-K1细胞中表达的在氨基酸425、418和405处截短的受体表现出与野生型受体相似的结合。在COS-7细胞中，405突变体的GIP依赖性cAMP产生减少。CHO-K1细胞中的最大cAMP产生用所有截短形式降低。在氨基酸400处截短的受体的结合是不可检测的;通过添加5个丙氨酸来增加尾长恢复结合和信号传导。通过丙氨酸扫描邻近跨膜结构域7的残基394-401产生的突变体都是功能性的。CT截短30个或更多个氨基酸，丝氨酸426/427突变，单独或组合，或完全CT丝氨酸敲除都降低受体内化率。因此，大多数GIP受体CT不是信号传导所需的，受体表达需要至少10405个氨基酸的链长，并且丝氨酸426和427对于调节受体内化速率是重要的。
Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone involved in the regulation of insulin secretion. In non-insulin-dependent diabetes mellitus insulin responses to GIP are blunted, possibly due to altered signal transduction or reduced receptor number. Site-directed mutagenesis was used to construct truncated GIP receptors to study the importance of the carboxyl-terminal tail (CT) in binding, signaling, and receptor internalization. Receptors truncated at amino acids 425, 418, and 405, expressed in COS-7 or CHO-K1 cells, exhibited similar binding to wild type receptors. GIP-dependent cAMP production with the 405 mutant was decreased in COS-7 cells. Maximal cAMP production in CHO-K1 cells was reduced with all truncated forms. Binding was undetectable with a receptor truncated at amino acid 400; increasing tail length by adding 5 alanines restored binding and signaling. Mutants produced by alanine scanning of residues 394–401, adjacent to transmembrane domain 7, were all functional. CT truncation by 30 or more amino acids, mutation of serines 426/427, singly or combined, or complete CT serine knockout all reduced receptor internalization rate. The majority of the GIP receptor CT is therefore not required for signaling, a minimum chain length of ∼405 amino acids is needed for receptor expression, and serines 426 and 427 are important for regulating rate of receptor internalization.
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DOI：
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发表时间：
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期刊：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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