HUMAN EOSINOPHIL MAJOR BASIC-PROTEIN IS AN ENDOGENOUS ALLOSTERIC ANTAGONIST AT THE INHIBITORY MUSCARINIC M2-RECEPTOR
HUMAN EOSINOPHIL MAJOR BASIC-PROTEIN IS AN ENDOGENOUS ALLOSTERIC ANTAGONIST AT THE INHIBITORY MUSCARINIC M2-RECEPTOR
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DOI：
10.1172/jci116331
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发表时间：
1993-04-01
影响因子：
15.9
通讯作者：
FRYER, AD
中科院分区：
文献类型：
--
作者：
JACOBY, DB;GLEICH, GJ;FRYER, AD
本文研究了人嗜酸性粒细胞主要碱性蛋白(MBP)和其他嗜酸性粒细胞蛋白对[H-3]N-甲基东莨菪碱([H-3]NMS；1×10(-10)M)与心肌M_2受体和颌下腺M_3受体结合的影响。MBP抑制[H-3]NMS与M2受体的特异性结合，但不抑制与M3受体的特异性结合。MBP还以剂量依赖的方式抑制阿托品诱导的[H-3]-NMS-受体复合体的解离，表明MBP与M2受体的相互作用是变构的。MBP的这种作用表明，它可能是一种内源性变构抑制药，与M2受体结合。MBP对[H-3]NMS结合的抑制作用可通过结合和中和MBP的肝素可逆。嗜酸性粒细胞过氧化物酶(EPO)也抑制[H-3]NMS与M2受体的特异性结合，但不抑制与M3受体的结合，并抑制阿托品诱导的[H-3]NMS-受体复合体的解离。在摩尔基础上，EPO的效力不如MBP。嗜酸性粒细胞阳离子蛋白和嗜酸性粒细胞源性神经毒素均不影响[H-3]NMS与M2受体的结合。因此，MBP和EPO都是M2受体的选择性变构拮抗剂。这些蛋白的作用可能是哮喘M2受体功能障碍和迷走神经介导的支气管收缩增强的重要原因。
The effect of human eosinophil major basic protein (MBP), as well as other eosinophil proteins, on binding of [H-3]N-methylscopolamine ([H-3]NMS; 1 x 10(-10) M) to muscarinic M2 receptors in heart membranes and M3 receptors in submandibular gland membranes was studied. MBP inhibited specific binding of [H-3]NMS to M2 receptors but not to M3 receptors. MBP also inhibited atropine-induced dissociation of [H-3]-NMS-receptor complexes in a dose-dependent fashion, demonstrating that the interaction of MBP with the M2 muscarinic receptor is allosteric. This effect of MBP suggests that it may function as an endogenous allosteric inhibitor of agonist binding to the M2 muscarinic receptor. Inhibition of [H-3]NMS binding by MBP was reversible by treatment with heparin, which binds and neutralizes MBP. Eosinophil peroxidase (EPO) also inhibited specific binding of [H-3]NMS to M2 receptors but not to M3 receptors and inhibited atropine-induced dissociation of [H-3]NMS-receptor complexes. On a molar basis, EPO is less potent than MBP. Neither eosinophil cationic protein nor eosinophil-derived neurotoxin affected binding of [H-3]NMS to M2 receptors. Thus both MBP and EPO are selective allosteric antagonists at M2 receptors. The effects of these proteins may be important causes of M2 receptor dysfunction and enhanced vagally mediated bronchoconstriction in asthma.