The Cambridge physiologist John Newport Langley proposed in 1909 the presence of a “receptive substance” that mediated drug action. This idea remained hypothetical until two further breakthroughs – when Raymond P. Ahlquist proposed in 1948 the existence of two接收者for epinephrine (α- and β-adrenoceptors), and when drugs able to block such接收者were developed in 1965. Blockers were and still are instrumental to combat diseases. One of the first was propranolol, the first clinically useful β-adrenoceptor blocker, for which James Black was awarded the Nobel Prize in 1988.

我们现在知道GPCR在哺乳动物基因组中高度多样化（随着人类估计大约一千个GPCR基因 - 8％的人类蛋白质组！）

一种fter the discovery by Alfred G. Gilman (Nobel Prize in 1994) of G proteins, Langley’s “receptive substances” were identified as the G-protein-coupled receptor (GPCR) family of proteins. G proteins are found on the inner surface of the cell membrane and propagate into the cell a signal initiated by the binding of a hormone –for instance, epinephrine – to one of its cognate GPCRs on the cell surface.

分子生物学技术有助于鉴定氨基酸序列，结晶技术的显着进展有助于解决数十种GPCR的晶体结构，以与三聚体G蛋白偶联的七跨膜结构域蛋白质建立其原型单体结构。诺贝尔奖被授予Robert J. Lefkowitz和Brian K. Kobilka授予他们在这家蛋白质的工作时，GPCR Research的重要性是在2012年认可的。

我们现在知道GPCR在哺乳动物基因组中高度多样化（人类估计有大约一千个GPCR基因 - 8％的人蛋白质组!), and they are the target of about 30% of the drugs sold in Pharmacies. Despite all the significant advances, however, their role in mediating drug action and signal transduction into the cell is still not fully understood.

GPCR四重奏作为信令开关

我们对GPCR的信号功能感兴趣，特别是在对腺苷的受体中，最古老的激素之一。腺苷受体调节广泛的身体功能，包括能量和温度稳态和神经递质释放。但有趣的是，他们还在咖啡和可乐饮料中施用的咖啡因，茶叶中的茶叶和可可霉素中的茶叶中的效果调解。

与许多其他GPCR一样，哺乳动物中的腺苷受体是相关蛋白质的亚家族（a₁, A_2A, A_2BA.₃）。除了功能性奇异单位（单体）之外，这些可以形成，所述高阶络合物（低聚物）由多个相等（HOMO）或不同（杂）单体组成。因此，我们想到进行研究以了解GPCR二聚体/低聚物存在于自然界的原因。

In two contributions published inBMC Biology, we have now shown that the minimal unit of the adenosine sensor device is constituted by four receptors, two A₁r和两个a_2AR, simultaneously coupled to two G proteins, one G_i和one G_s。

The origin of the current discovery started 12 years ago after a serendipitous finding. With the aim of showing a lack of interaction between A₁R, which is coupled to the G_i蛋白质（介导腺苷酸环酶的抑制和营地减少），以及一个_2AR, which is coupled to G_s（介导腺苷酸环酶的激活和营地的增加），我们发现相反。一种₁R and A_2AR do form heteromers, with a signaling output that cannot be accounted for as the sum of signals from its constituents signaling.This confers A₁R-A_2AR复合能够充当腺苷浓度的敏感传感器，培养细胞和大脑中的神经末端。然而，实现这一点的机制尚不清楚。

In two contributions published inBMC Biology, we have now shown that the minimal unit of the adenosine sensor device is constituted by four receptors, two A₁r和两个a_2AR, simultaneously coupled to two G proteins, one G_i和one G_s。将实验与计算模型相结合我们提出了由紧凑型菱形异质蛋白组成的整体结构。

In the second contribution, we have shown the mechanism by which the sensor works at the molecular level. Due to A₁R’s higher affinity for the hormone, adenosine at a low concentration binds predominantly to A₁R, engaging G_i-mediated signaling, which significantly decreases cAMP accumulation (left panel). However, at higher concentrations, adenosine progressively binds to A_2Ar（中间板），直到饱和浓度，全部占用A.₁R and A_2AR, there is a marked increase in cAMP levels because G_s在g时被激活_iis blocked. Our structural model suggests that in the compact tetrameric complex, the C-terminal tail of the activated A_2A受体可以防止同时激活g_s和G._i，领先优先g_s耦合。

一种challenge for the 21^stcentury is to understand how other GPCR (hetero)oligomers influence the physiological role of receptors, and to assess their potential as therapeutic targets. The several hundred GPCRs in higher organisms already provide diversity but we now need to also consider what are the novel properties arising when GPCRs form heteromers. The number of identified heteromers isnow counted by hundreds, and they include receptors for peptides and photons as well as hormones. Clearly, the possibility of targeting or disrupting physiologically relevant GPCR heteromers provides new opportunities for novel drug discovery.