m1毒蕈碱受体第二跨膜结构域两个高度保守的酪氨酸残基在配体结合和受体功能中的作用。

Receptors & signal transduction Pub Date : 1996-01-01
S Y Lee, S Z Zhu, E E el-Fakahany
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引用次数: 0

摘要

毒蕈碱乙酰胆碱受体含有两个高度保守的酪氨酸残基,它们位于第二跨膜结构域的胞外边界内或外,是G蛋白偶联受体亚家族所特有的。这些酪氨酸残基位于毒蕈碱受体m1亚型序列的82位和85位。在本文中,我们研究了这两个残基参与配体结合和激动剂诱导的激活该受体亚型使用定点诱变。我们的数据首次表明这两种酪氨酸在毒蕈碱受体功能中的重要作用。也有证据表明,尽管这些酪氨酸残基的芳香部分在拮抗剂结合中起作用,但该部分和酪氨酸酚羟基都参与激动剂结合和受体激活。结果讨论了这两个酪氨酸残基与其他位于不同跨膜段的保守酪氨酸部分的可能关系。所有这些残基可能在配体结合和受体激活过程中协同作用,尽管程度不同。目前的研究结果有望进一步加深我们目前对参与这些过程的毒蕈碱受体结构域的理解。
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Role of two highly conserved tyrosine residues in the m1 muscarinic receptor second transmembrane domain in ligand binding and receptor function.

Muscarinic acetylcholine receptors contain two highly conserved tyrosine residues that are located within or at the extracellular border of the second transmembrane domain and are unique to this subfamily of G protein-coupled receptors. These tyrosine residues are located at positions 82 and 85 of the sequence of the m1 subtype of muscarinic receptors. In this article, we studied the involvement of these two residues in ligand binding to and agonist-induced activation of this receptor subtype using site-directed mutagenesis. Our data suggest for the first time an important role of these two tyrosines in muscarinic receptor function. Evidence is also provided that although the aromatic moiety of these tyrosine residues plays a role in antagonist binding, both this moiety and the tyrosine phenolic hydroxyl group are involved in agonist binding and receptor activation. The results are discussed in terms of a possible relationship of these two tyrosine residues and other conserved tyrosine moieties located in different transmembrane segments. All of these residues might contribute in concert, albeit to different degrees, to the process of ligand binding and receptor activation. The present findings are expected to further our current understanding of the muscarinic receptor domains involved in these processes.

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