The structural basis of G-protein-coupled receptor signaling (Nobel Lecture).
The structural basis of G-protein-coupled receptor signaling (Nobel Lecture).
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DOI：
10.1002/anie.201302116
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发表时间：
2013-06-17
影响因子：
16.6
通讯作者：
Kobilka, Brian
中科院分区：
文献类型：
--
作者：
Kobilka, Brian
复杂的生物体需要一个复杂的通讯网络来维持体内平衡。来自我们身体不同部位的细胞通过激素和神经递质形式的化学信使相互交流。细胞使用位于质膜上的G蛋白偶联受体（GPCR）处理这些化学信息中编码的信息。GPCR还介导与外部世界的通信。视觉、嗅觉和味觉是由GPCR介导的。GPCR是自然界最通用的化学传感器。在人类基因组中有超过800个GPCR，它们对广泛的化学实体做出反应，从光子，质子和钙离子，小的有机分子GPCR的经典作用是检测细胞外激动剂的存在，将信息传递穿过质膜，并激活细胞质异源三聚体G蛋白，导致下游效应蛋白的调节。以人β2肾上腺素能受体（β2AR）为例，肾上腺素的结合导致Gαs活化、腺苷酸环化酶刺激、cAMP蓄积、PKA活化和参与细胞代谢的蛋白质磷酸化（图1）。然而，大量的研究表明，许多GPCR具有更复杂的信号库。例如，β 2 AR在心肌细胞中与Gαs和Gαi偶联，[1]并且还可以通过抑制蛋白以G蛋白非依赖性方式通过MAP激酶途径发出信号。[2，3]类似地，GPCR脱敏的过程涉及多个途径，包括受体磷酸化事件、抑制蛋白介导的内化到内体中、受体再循环和溶酶体降解。GPCR寡聚化的可能性[4]和受体定位于特定的膜区室使这些活性进一步复杂化
Complex organisms require a sophisticated communication network to maintain homeostasis. Cells from different parts of our bodies communicate with each other using chemical messengers in the form of hormones and neurotransmitters. Cells process information encoded in these chemical messages using G-protein-coupled receptors (GPCRs) located in the plasma membrane. GPCRs also mediate communication with the outside world. The senses of sight, smell and taste are mediated by GPCRs. GPCRs are nature's most versatile chemical sensors. There are over 800 GPCRs in the human genome and they respond to a broad spectrum of chemical entities ranging from photons, protons and calcium ions, small organic molecules (including odorants and neurotransmitters), to peptides and glycoproteins.The classical role of a GPCR is to detect the presence of an extracellular agonist, transmit the information across the plasma membrane, and activate a cytoplasmic heterotrimeric G protein, leading to modulation of downstream effector proteins. Taking the human β2 adrenergic receptor (β2AR) as an example, binding of adrenaline leads to activation of Gαs, stimulation of adenylyl cyclase, cAMP accumulation, PKA activation, and phosphorylation of proteins involved in cell metabolism (Figure 1). However, a wealth of research has now demonstrated that many GPCRs have more complex signaling repertoires. For example, the β2AR couples to both Gαs and Gαi in cardiac myocytes,[1] and can also signal through MAP kinase pathways in a G-protein-independent manner via arrestin.[2, 3] Similarly, the process of GPCR desensitization involves multiple pathways, including receptor phosphorylation events, arrestin-mediated internalization into endosomes, receptor recycling, and lysosomal degradation. These activities are further complicated by the possibility of GPCR oligomerization,[4] and the localization of receptors to specific membrane compartments
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影响因子：
56.9
作者：
KOBILKA, BK;KOBILKA, TS;LEFKOWITZ, RJ
通讯作者：
LEFKOWITZ, RJ
影响因子：
4.8
作者：
Ghanouni, P;Gryczynski, Z;Kobilka, BK
通讯作者：
Kobilka, BK
影响因子：
4.8
作者：
Gether, U;Ballesteros, JA;Kobilka, BK
通讯作者：
Kobilka, BK
影响因子：
11.4
作者：
Gether, U;Lin, S;Kobilka, BK
通讯作者：
Kobilka, BK
影响因子：
64.8
作者：
Granier, Sebastien;Manglik, Aashish;Kruse, Andrew C.;Kobilka, Tong Sun;Thian, Foon Sun;Weis, William I.;Kobilka, Brian K.
通讯作者：
Kobilka, Brian K.