G protein antagonists. A novel hydrophobic peptide competes with receptor for G protein binding.
G protein antagonists. A novel hydrophobic peptide competes with receptor for G protein binding.
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DOI：
10.1016/s0021-9258(18)41991-6
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发表时间：
1992-08
期刊：
影响因子：
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通讯作者：
Hidehito MukaiSj;Eisuke Munekataq;Tsutomu HigashijimaS
中科院分区：
文献类型：
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作者：
Hidehito MukaiSj;Eisuke Munekataq;Tsutomu HigashijimaS
P 物质 (SP) 类似物 [D-Pro4,D-Trp7,9,10] SP4-11 已知可抑制各种结构上不相关的信使分子以及 SP 的作用。我们对该肽对受体调节纯化G蛋白的影响的研究表明，该肽的至少一些生物学效应可以通过该肽阻断受体激活G蛋白的能力来解释。在此，我们报道了一种新型截短的 SP 相关肽 pGlu-Gln-D-Trp-Phe-D-Trp-D-Trp-Met-NH2，可抑制重构磷脂囊泡中 M2 毒蕈碱胆碱能受体 (M2 mAChR) 激活 G(i) 或 G(o) 或抑制 β 肾上腺素受体激活 Gs，通过受体促进的 GTP 水解。肽的抑制作用显然是可逆的，并且与受体与 G 蛋白的结合具有竞争性；这种抑制作用可以通过增加囊泡中受体的浓度来克服，并且不会因G蛋白浓度的变化而改变。肽的竞争效应用于分析激动剂对受体-G 蛋白相互作用的影响。毒蕈碱激动剂的浓度变化并没有改变该肽对G(o)对M2 mAChR促进的GTP酶的抑制作用，这与激动剂增加受体的调节效率但不改变其对G蛋白的亲和力的观点是一致的。这组新化合物（G 蛋白拮抗剂）是定量研究受体-G 蛋白相互作用的有前途的工具。
A substance P (SP) analog, [D-Pro4,D-Trp7,9,10] SP4-11, is known to inhibit the actions of various structurally unrelated messenger molecules as well as SP. Our studies on the effects of this peptide on the regulation of purified G proteins by receptor showed that at least some of the biological effects of the peptide can be explained by the ability of the peptide to block the activation of G proteins by receptors. Here we report that a novel truncated SP-related peptide, pGlu-Gln-D-Trp-Phe-D-Trp-D-Trp-Met-NH2, inhibited the activation of G(i) or G(o) by M2 muscarinic cholinergic receptor (M2 mAChR) or of Gs by beta-adrenergic receptor in the reconstituted phospholipid vesicles, assayed by receptor-promoted GTP hydrolysis. The inhibition by the peptide was apparently reversible and competitive with respect to receptor binding to G proteins; the inhibition could be overcome by increasing the concentration of receptor in the vesicles and was not altered by changes in the concentration of G protein. The competing effects of the peptide were used to analyze the effect of agonist on receptor-G protein interaction. The concentration change of muscarinic agonist did not alter the inhibitory effects of the peptide on M2 mAChR-promoted GTPase by G(o), which is consistent with the idea that agonist increases the regulatory efficiency of the receptor but does not alter its affinity for G proteins. This new group of compounds (G protein antagonists) is a promising tool to study receptor-G protein interaction quantitatively.