Baker Jillian G
Institute of Cell Signaling, Medical School, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom.
Mol Pharmacol. 2005 Dec;68(6):1645-55. doi: 10.1124/mol.105.015461. Epub 2005 Aug 29.
There are three members of the beta-adrenoceptor family, all of which are primarily coupled to G(s) proteins. Recent studies using the huge range of beta-ligands now available have given remarkable new insights into their pharmacology. beta1-adrenoceptors exist in at least two active conformations, whereas beta2-adrenoceptors are able to induce signaling via different agonist-induced receptor conformational states, and their affinity for antagonists can be altered by highly efficacious agonists. This study therefore examined the pharmacology of the human beta3-adrenoceptor stably expressed in Chinese hamster ovary cells. Several compounds described previously as beta-antagonists have agonist properties at the beta3-adrenoceptor. Antagonist affinity measurements varied at the beta3-adrenoceptor in a manner similar to those observed at human beta1-adrenoceptors and unlike those seen at beta2-adrenoceptors. Some ligands (e.g., fenoterol and cimaterol) were more readily inhibited by all antagonists, whereas other ligands [e.g., alprenolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride [SR 59230A]) stimulated responses that were more resistant to antagonism. Alprenolol inhibited fenoterol-induced beta3-adrenoceptor responses while acting as an agonist at higher concentrations. This is highly suggestive of two active conformational states of the beta3-adrenoceptor. (S)-4-[2-Hydroxy-3-phenoxypropylaminoethoxy]-N-(2-methoxyethyl)phenoxyacetamide (ZD 7114) stimulated a two-component response, of which the first component was more readily antagonized than the second. Taken together, these experiments suggest that the human beta3-adrenoceptor exists in at least two different agonist conformations with a similar high- and low-affinity pharmacology analogous to, if not as pronounced as, the beta1-adrenoceptor. Both conformations are present in living cells and can be distinguished by their pharmacological characteristics. In this respect, the human beta3-adrenoceptor seems similar to the human beta1-adrenoceptor.
β-肾上腺素能受体家族有三个成员，它们主要都与G(s)蛋白偶联。近期利用现有的大量β-配体进行的研究，为其药理学带来了显著的新见解。β1-肾上腺素能受体至少以两种活性构象存在，而β2-肾上腺素能受体能够通过不同的激动剂诱导的受体构象状态引发信号传导，并且它们对拮抗剂的亲和力可被高效激动剂改变。因此，本研究检测了稳定表达于中国仓鼠卵巢细胞中的人β3-肾上腺素能受体的药理学特性。几种先前被描述为β-拮抗剂的化合物在β3-肾上腺素能受体上具有激动剂特性。拮抗剂亲和力测量在β3-肾上腺素能受体上的变化方式，与在人β1-肾上腺素能受体上观察到的相似，而与在β2-肾上腺素能受体上看到的不同。一些配体（如非诺特罗和西马特罗）更容易被所有拮抗剂抑制，而其他配体[如阿普洛尔和1-(2-乙基苯氧基)-3-[[(1S)-1,2,3,4-四氢-1-萘基]氨基]-(2S)-2-丙醇盐酸盐[SR 59230A]]刺激的反应对拮抗作用更具抗性。阿普洛尔在抑制非诺特罗诱导的β3-肾上腺素能受体反应的同时，在较高浓度时表现为激动剂。这强烈提示β3-肾上腺素能受体存在两种活性构象状态。(S)-4-[羟基-3-苯氧基丙基氨基乙氧基]-N-(2-甲氧基乙基)苯氧基乙酰胺(ZD 7114)刺激了一种双组分反应，其中第一组分比第二组分更容易被拮抗。综上所述，这些实验表明人β3-肾上腺素能受体至少以两种不同的激动剂构象存在，其具有与β1-肾上腺素能受体相似的高亲和力和低亲和力药理学特性，即便不那么明显。两种构象都存在于活细胞中，并且可通过其药理学特征加以区分。在这方面，人β3-肾上腺素能受体似乎与人类β1-肾上腺素能受体相似。
