The β-adrenoceptor
The β-adrenoceptor
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DOI：
10.1164/ajrccm.158.supplement_2.13tac110
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发表时间：
1998-11-01
影响因子：
24.7
通讯作者：
Johnson, M
中科院分区：
文献类型：
--
作者：
Johnson, M
人类β-肾上腺素受体是七跨膜受体家族的成员，由5号染色体上的基因编码。β-肾上腺素受体分为β(1)、β(2)和β(3)亚组，其中β(2)受体广泛分布在呼吸道中，特别是气道平滑肌中。 β(2)-肾上腺素受体激活后的细胞内信号传导很大程度上受到与腺苷酸环化酶偶联的三聚体 Cs 蛋白的影响。环磷酸腺苷 (cAMP) 通过肌肉调节蛋白的磷酸化和细胞 Ca2+ 浓度的减弱来诱导气道松弛。还描述了涉及膜 maxi-K+ 通道激活和通过 Gi 与 MAP 激酶系统偶联的替代 cAMP 独立途径。定点诱变已将第三和第四膜域内的 Asp 113 和 Ser 204/207 鉴定为 β(2) 受体的活性位点，对于 β(2) 激动剂的结合和活性至关重要。 β(2)-激动剂的特征是直接激活受体的激动剂（沙丁胺醇）、被吸收到膜库中的激动剂（福莫特罗）以及与受体特异性辅助结合位点相互作用的激动剂（沙美特罗）。这些作用机制的差异反映在哮喘患者气道平滑肌松弛和支气管扩张的动力学上。与β(2)激动剂激活相关的β-肾上腺素受体脱敏是β-ARK磷酸化以及β-抑制蛋白结合后受体与Gs解偶联的结果，是受体通过隔离、再敏化和下调过程内化和再循环的结果，通过对受体基因表达的影响进行调节。受体脱敏程度似乎有所不同，具体取决于细胞或组织类型，并反映在对长期 β(2) 激动剂治疗的临床耐受性的不同特征中。已经描述了 β(2) 受体的许多多态性，这些多态性似乎会改变激动剂暴露后受体的行为。其中包括 Arg-Gly 16、Glu-Gln 27 和 Thr-Ile 164。Gly 16 受体下调程度更大，并与气道高反应性增加、夜间症状和更严重的哮喘相关。 Glu 27 形式似乎可以防止下调，并与反应性较低的气道相关。对于给定的多态性，个体可以是纯合的或杂合的，并且必须对大量人群进行研究以确定它们对哮喘表型的重要性。
The human beta-adrenoceptor is a member of the seven-transmembrane family of receptors, encoded by a gene on chromosome 5. beta-Adrenoceptors have been classified into beta(1), beta(2), and beta(3) subgroups, with beta(2)-receptors being widely distributed in the respiratory tract, particularly in airway smooth muscle. Intracellular signaling following beta(2)-adrenoceptor activation is largely affected through a trimeric Cs protein coupled to adenylate cyclase. Cyclic AMP (cAMP) induces airway relaxation through phosphorylation of muscle regulatory proteins and attenuation of cellular Ca2+ concentrations. Alternative cAMP-independent pathways involving activation of membrane maxi-K+ channels and coupling through Gi to the MAP kinase system have also been described. Site-directed mutagenesis has identified Asp 113 and Ser 204/207 within the third and fourth membrane domains as the active site of the beta(2)-receptor, critical for beta(2)-agonist binding and activity. beta(2)-Agonists have been characterized as those that directly activate the receptor (albuterol), those that are taken up into a membrane depot (formoterol), and those that interact with a receptor-specific auxiliary binding site (salmeterol). These differences in mechanism of action are reflected in the kinetics of airway smooth muscle relaxation and bronchodilation in patients with asthma. beta-Adrenoceptor desensitization associated with beta(2)-agonist activation is a consequence of phosphorylation by beta-ARK and uncoupling of the receptor from Gs following beta-arrestin binding, of internalization and recycling of the receptor through processes of sequestration and resensitization and downregulation, modulated by an effect on receptor gene expression. The degree of receptor desensitization appears to differ, depending on the cell or tissue type, and is reflected in the different profiles of clinical tolerance to chronic beta(2)-agonist therapy, A number of polymorphisms of the beta(2)-receptor have been described that appear to alter the behavior of the receptor following agonist exposure. These include Arg-Gly 16, Glu-Gln 27, and Thr-Ile 164. The Gly 16 receptor downregulates to a greater extent and is associated with increased airway hyperreactivity, nocturnal symptoms, and more severe asthma. The Glu 27 form appears to protect against downregulation and is associated with less reactive airways. An individual can be homozygous or heterozygous for given polymorphisms, and large populations will have to be studied to determine their importance to the asthma phenotype.