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首页> 外文期刊>Biochemical Pharmacology >Defects of tyrosine289phenylalanine mutation on binding and functional properties of the human tachykinin NK2 receptor stably expressed in chinese hamster ovary cells.
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Defects of tyrosine289phenylalanine mutation on binding and functional properties of the human tachykinin NK2 receptor stably expressed in chinese hamster ovary cells.

机译：酪氨酸289苯丙氨酸突变对中国仓鼠卵巢细胞中稳定表达的人类速激肽NK2受体的结合和功能特性的影响。

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摘要

A point mutation was made at position 289 in the transmembrane segment 7 of the human tachykinin NK2 receptor to yield a tyrosine/phenylalanine (Tyr/Phe) substitution. Chinese hamster ovary cells stably transfected with the wild-type or Tyr289Phe mutant NK2 receptor both bound neurokinin A (NKA) and the synthetic NK2 receptor-selective agonists, GR 64349 and [betaAla8]NKA(4-10), with high and even affinities. Neurokinin B (NKB) and substance P (SP) also displayed sizeable binding affinities, albeit with lower affinity as compared to NKA. In a functional assay (production of inositol-1,4,5-trisphosphate, IP3), NKA, GR 64349, and [betaAla8]INKA(4-10) stimulated IP3 accumulation via the wild-type and mutant receptors with similar potencies. On the other hand, NKB and SP exhibited a dramatic reduction in their agonist efficacies at the mutant receptor, NKB acting as a partial agonist (maximum effect = 50% of the response to NKA) and SP being totally inactive. The results obtained with phenoxybenzamine inactivation experiments indicated that a large and similar receptor reserve existed for both the wild-type and the mutant receptor. SP, which displayed sizeable binding affinity for the mutant receptor but did not stimulate IP3 accumulation, antagonized the agonist effect of NKA. The antagonist action of SP at the mutant NK2 receptor cannot be ascribed to receptor internalization. The Tyr/Phe replacement at position 289 markedly reduced the binding affinity and antagonist potency of the non-peptide ligand, SR 48968, without affecting the binding affinity and antagonist potency of the bicyclic peptide antagonist MEN 11420. The results indicate that the hydroxyl radical function of Tyr289 in transmembrane segment 7 of the human NK2 receptor is, directly or indirectly, involved in stimulus transduction when the NK2 receptor is occupied by NKB or SP, but not when using NKA or NK2 receptor-selective agonists.
机译：在人速激肽NK2受体跨膜片段7的289位进行点突变，以产生酪氨酸/苯丙氨酸（Tyr / Phe）取代。用野生型或Tyr289Phe突变NK2受体稳定转染的中国仓鼠卵巢细胞均结合了神经激肽A（NKA）和合成的NK2受体选择性激动剂GR 64349和[betaAla8] NKA（4-10），具有很高的亲和力。神经激肽B（NKB）和物质P（SP）也显示了相当大的结合亲和力，尽管与NKA相比亲和力较低。在功能测定（肌醇-1,4,5-三磷酸肌醇，IP3的产生）中，NKA，GR 64349和βAla8] INKA（4-10）通过具有相似效力的野生型和突变受体刺激IP3积累。另一方面，NKB和SP在突变受体上的激动剂效力显着降低，NKB作为部分激动剂（最大作用=对NKA的响应的50％），而SP完全没有活性。苯氧基苯甲胺灭活实验获得的结果表明，野生型和突变型受体均存在大量相似的受体储备。对突变受体表现出相当大的结合亲和力但不刺激IP3积累的SP拮抗NKA的激动作用。 SP对突变NK2受体的拮抗作用不能归因于受体内在化。在位置289处的Tyr / Phe替换显着降低了非肽配体SR 48968的结合亲和力和拮抗剂效能，而没有影响双环肽拮抗剂MEN 11420的结合亲和力和拮抗剂效能。结果表明，羟基自由基的功能当NK2受体被NKB或SP占据时，人类NK2受体跨膜片段7中的Tyr289的直接或间接参与刺激转导，但当使用NKA或NK2受体选择性激动剂时则不参与。

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