Constitutive activation of the cyclic adenosine 3',5'-monophosphate signaling pathway by parathyroid hormone (PTH)/PTH-related peptide receptors mutated at the two loci for Jansen's metaphyseal chondrodysplasia.
Constitutive activation of the cyclic adenosine 3',5'-monophosphate signaling pathway by parathyroid hormone (PTH)/PTH-related peptide receptors mutated at the two loci for Jansen's metaphyseal chondrodysplasia.
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DOI：
10.1210/mend.11.7.9934
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发表时间：
1997-06
影响因子：
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通讯作者：
E. Schipani;G. Jensen;J. Pincus;R. Nissenson;T. Gardella;H. Jüppner
中科院分区：
文献类型：
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作者：
E. Schipani;G. Jensen;J. Pincus;R. Nissenson;T. Gardella;H. Jüppner
两种不同的激活PTH/PTH相关肽（PTHrP）受体突变，H223 R和T410 P，最近被确定为詹森干骺端软骨发育不良的最可能原因。为了评估人PTH/PTHrP受体中任一氨基酸位置的功能重要性，将H223和T410分别替换为所有其他氨基酸。在位置223处，仅精氨酸和赖氨酸导致激动剂非依赖性cAMP积累;所有其他氨基酸取代导致缺乏组成型活性或由于细胞表面表达差而无信息的受体突变体。相比之下，大多数氨基酸取代位置410赋予组成型cAMP积累和影响PTH/PTHrP受体表达根本没有或只是温和的。对应于人PTH/PTHrP受体中的H223R或T410P交换的突变在引入负鼠受体同源物时也导致组成型活性，但在引入大鼠PTH/PTHrP受体时基础cAMP积累显示很少或没有变化。在詹森病中突变的PTH/PTHrP受体残基在该G蛋白偶联受体家族的所有哺乳动物成员中是保守的。然而，当H223R或T410P突变的等价物被引入到其他几个相关受体中时，包括PTH 2受体和降钙素、促胰液素、GH释放激素、胰高血糖素样肽I和CRH的受体，所产生的突变体未能诱导组成型活性。这些研究表明，在人PTH/PTHrP受体，223和410，有两个残基在信号转导中的关键作用，但不同的序列约束。
Two different activating PTH/PTH-related peptide (PTHrP) receptor mutations, H223R and T410P, were recently identified as the most likely cause of Jansen's metaphyseal chondrodysplasia. To assess the functional importance of either amino acid position in the human PTH/PTHrP receptor, H223 and T410 were individually replaced by all other amino acids. At position 223, only arginine and lysine led to agonist-independent cAMP accumulation; all other amino acid substitutions resulted in receptor mutants that lacked constitutive activity or were uninformative due to poor cell surface expression. In contrast, most amino acid substitutions at position 410 conferred constitutive cAMP accumulation and affected PTH/PTHrP receptor expression not at all or only mildly. Mutations corresponding to the H223R or T410P exchange in the human PTH/PTHrP receptor also led to constitutive activity when introduced into the opossum receptor homolog, but showed little or no change in basal cAMP accumulation when introduced into the rat PTH/PTHrP receptor. The PTH/PTHrP receptor residues mutated in Jansen's disease are conserved in all mammalian members of this family of G protein-coupled receptors. However, when the equivalent of either the H223R or the T410P mutation was introduced into several other related receptors, including the PTH2 receptor and the receptors for calcitonin, secretin, GH-releasing hormone, glucagon-like peptide I, and CRH, the resulting mutants failed to induce constitutive activity. These studies suggest that two residues in the human PTH/PTHrP receptor, 223 and 410, have critical roles in signal transduction, but with different sequence constrains.