N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine inhibits ligand binding to certain G protein-coupled receptors.
N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine inhibits ligand binding to certain G protein-coupled receptors.
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N,N,N,N-四(2-吡啶基甲基)乙二胺抑制配体与某些 G 蛋白偶联受体的结合。
DOI：
10.1016/s0014-2999(03)02005-3
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发表时间：
2003
影响因子：
5
通讯作者：
Wojcikiewicz,RichardJH
中科院分区：
文献类型：
--
作者：
Webster,JackM;Bentley,MatthewT;Wojcikiewicz,RichardJH
N，N，N′，N′-四（2-吡啶基甲基）乙二胺（TPEN）是一种广泛应用于生物体系中的重金属螯合剂。在这里，我们表明，TPEN抑制配体结合某些G蛋白偶联受体，是一种拮抗剂在毒蕈碱受体。在完整的人神经母细胞瘤SH-SY 5 Y细胞中，毒蕈碱受体配体[N-甲基-3H]东莨菪碱甲基氯化物的结合被TPEN抑制（Ki <26 μM），毒蕈碱受体激动剂诱导的肌醇1，4，5-三磷酸形成（Ki <26 μM）也是如此。这种拮抗作用不是由于金属离子螯合，表明它是由TPEN与毒蕈碱受体的直接相互作用引起的。对TPEN对SH-SY 5 Y细胞膜制备物中其他受体的影响的检查表明，非肽类阿片受体配体[15，16 - 3 H]二丙诺啡的结合被强烈抑制，而[125 I]血管活性肠多肽的结合则没有。这种模式的选择性也被认为是在AR 4 - 2 J大鼠胰腺癌细胞膜，其中TPEN抑制配体结合毒蕈碱受体，但不是胆囊收缩素受体。总之，这些数据表明TPEN抑制配体与某些G蛋白偶联受体的结合，并对那些跨膜螺旋形成配体相互作用的主要位点的受体表现出选择性。TPEN可能对这类G蛋白偶联受体具有广泛的拮抗活性。
N,N,N′,N′-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) is used widely in biological systems to chelate certain heavy metals, particularly Zn2+. Here we show that TPEN inhibits ligand binding to certain G protein-coupled receptors and is an antagonist at muscarinic receptors. In intact human neuroblastoma SH-SY5Y cells, the binding of the muscarinic receptor ligand [N-methyl-3H]scopolamine methyl chloride was inhibited by TPEN (Ki∼26 μM), as was muscarinic receptor agonist-induced inositol 1,4,5-trisphosphate formation (Ki∼26 μM). This antagonism was not due to metal ion chelation, indicating that it resulted from a direct interaction of TPEN with muscarinic receptors. Examination of the effects of TPEN on other receptors in SH-SY5Y cell membrane preparations showed that the binding of the nonpeptide opioid receptor ligand [15,16-3H]diprenorphine was strongly inhibited, whereas binding of [125I]vasoactive intestinal polypeptide was not. This pattern of selectivity was also seen in AR4-2J rat pancreatoma cell membranes, in which TPEN inhibited ligand binding to muscarinic receptors, but not that to cholecystokinin receptors. In conclusion, these data show that TPEN inhibits ligand binding to certain G protein-coupled receptors and exhibits selectivity towards those receptors whose transmembrane helices form the predominant site for ligand interaction. TPEN may have widespread antagonistic activity towards G protein-coupled receptors of this kind.