ANTAGONISTS WITH NEGATIVE INTRINSIC ACTIVITY AT DELTA-OPIOID RECEPTORS COUPLED TO GTP-BINDING PROTEINS
ANTAGONISTS WITH NEGATIVE INTRINSIC ACTIVITY AT DELTA-OPIOID RECEPTORS COUPLED TO GTP-BINDING PROTEINS
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DOI：
10.1073/pnas.86.19.7321
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发表时间：
1989-10-01
影响因子：
11.1
通讯作者：
HERZ, A
中科院分区：
文献类型：
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作者：
COSTA, T;HERZ, A
根据药物 - 受体相互作用的经典模型，竞争性拮抗剂与激动剂一样，具有结合受体分子上共同位点的能力。然而，它们与激动剂不同，因为它们不能引发导致生物反应的“刺激”，即它们缺乏内在活性。对于那些其信号通过GTP结合调节蛋白（G蛋白）转导至效应系统的受体，这种刺激的一种机制等效物是激动剂结合的受体加速核苷酸交换从而增强G蛋白分子上GTP酶活性的能力。在此我们表明，对于这类受体家族的一个成员（NG108 - 15神经母细胞瘤 - 胶质瘤细胞膜中的δ阿片受体），可以区分出两种类型的竞争性拮抗剂。一种类型没有内在活性，因为它既不刺激也不抑制G蛋白的GTP酶活性，并且其对受体的表观亲和力不会因百日咳毒素介导的受体与G蛋白的解偶联而改变。然而，第二种类型可以抑制GTP酶，因此表现出负内在活性；它与受体的亲和力在与G蛋白解偶联后增加。具有负内在活性的拮抗剂的存在可能是几类神经递质或激素受体的一个普遍特征，并要求对竞争性拮抗剂产生的生物学效应进行重新评估。
According to classical models of drug-receptor interactions, competitive antagonists share with agonists the ability to bind to a common site on the receptor molecule. However, they are different from agonists, as they cannot trigger the "stimulus" that leads to biological responses-i.e., they lack intrinsic activity. For those receptors whose signals are transduced to effector systems by GTP-binding regulatory proteins (G proteins), a mechanistic equivalent of such a stimulus is an increased ability of agonist-bound receptor to accelerate nucleotide exchange and thus GTPase activity on the G-protein molecule. Here we show that for a member of this family of receptors (.delta. opioid receptors in membranes of NG108-15 neuroblastoma-glioma cells), two types of competitive antagonists can be distinguished. One type has no intrinsic activity, since it neither stimulates nor inhibits the GTPase activity of G proteins and its apparent affinity for the receptor is not altered by pertussis toxin-mediated uncoupling of receptor and G protein. The second type, however, can inhibit GTPase and thus exhibits negative intrinsic activity; its affinity for receptors is increased following uncoupling from G proteins. The existence of antagonists with negative intrinsic activity may be a general feature of several classes of neurotransmitters or hormone receptors and calls for a reevaluation of biological effects produced by competitive antagonists.