Agonist interactions with chimeric and mutant beta1- and beta3-adrenergic receptors: involvement of the seventh transmembrane region in conferring subtype specificity.
Agonist interactions with chimeric and mutant beta1- and beta3-adrenergic receptors: involvement of the seventh transmembrane region in conferring subtype specificity.
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发表时间：
1998-05
影响因子：
3.6
通讯作者：
J. Granneman;K. Lahners;Y. Zhai
中科院分区：
文献类型：
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作者：
J. Granneman;K. Lahners;Y. Zhai
β 1-和β 3-肾上腺素能受体（AR）是脂肪细胞中主要的β-AR亚型，对天然和重组β-AR的分析揭示了这些亚型之间的几种药理学和生物化学差异。本研究使用在中国仓鼠卵巢细胞中表达的嵌合和突变的大鼠β-AR，以检查儿茶酚胺和原型β 3-AR激动剂的激动剂性质的某些特征差异的基础。β-AR亚型之间跨膜（TM）区域6以外的序列交换对原型β 3-AR激动剂BRL 37，344和CL 316，243的亲和力和功效具有显著的相互作用，而不影响与儿茶酚胺的相互作用。在β 1-AR的TM 7中Phe 350和Phe 351突变为在β 3-AR中发现的Ala和Leu足以允许原型β 3-AR激动剂激活。有趣的是，该突变不影响儿茶酚胺作用，也不损害普萘洛尔阻断异丙肾上腺素或选择性β 3-AR激动剂作用的能力。来自预测的TM 5至TM 6的含有β 3-AR序列的β 1-AR显示出降低的对儿茶酚胺的亲和力，而不改变激动剂效力，表明增强的偶联效率。然而，在β 3-AR中包含同源β 1-AR序列并没有产生相互作用。这些结果是第一个定义的β 3-AR亚型选择性激动TM 7的主要决定因素，并表明，选择性苯乙醇胺，儿茶酚胺，和普萘洛尔行动的决定因素是不同的。
beta1- and beta3-adrenergic receptors (AR) are the predominant beta-AR subtypes in adipocytes, and analysis of native and recombinant beta-AR has revealed several pharmacological and biochemical differences between these subtypes. This study used chimeric and mutated rat beta-AR expressed in Chinese hamster ovary cells to examine the basis of certain characteristic differences in the agonist properties of catecholamines and prototypic beta3-AR agonists. The exchange of sequence beyond transmembrane (TM) region 6 between the beta-AR subtypes had dramatic and reciprocal effects on the affinity and efficacy of the prototypic beta3-AR agonists BRL 37,344 and CL 316,243, without affecting the interactions with catecholamines. Mutation of Phe350 and Phe351 in TM7 of the beta1-AR to Ala and Leu found in the beta3-AR was sufficient to allow activation by prototypic beta3-AR agonists. Interestingly, this mutation did not affect catecholamine action and it did not impair the ability of propranolol to block the actions of isoproterenol or the selective beta3-AR agonists. beta1-AR containing beta3-AR sequence from predicted TM5 through TM6 exhibited reduced affinity for catecholamines without altering agonist potency, suggesting enhanced coupling efficiency. Inclusion of the homologous beta1-AR sequence in the beta3-AR, however, did not produce reciprocal effects. These results are the first to define a major determinant of beta3-AR subtype-selective agonism in TM7 and demonstrate that the determinants of selective phenethanolamines, catecholamines, and propranolol action are distinct.