Receptor-Receptor Interactions of G Protein-Coupled Receptors in the Carotid Body: A Working Hypothesis.
Receptor-Receptor Interactions of G Protein-Coupled Receptors in the Carotid Body: A Working Hypothesis.
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DOI：
10.3389/fphys.2018.00697
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发表时间：
2018
影响因子：
4
通讯作者：
De Caro R
中科院分区：
文献类型：
--
作者：
Porzionato A;Stocco E;Guidolin D;Agnati L;Macchi V;De Caro R
在颈动脉小体(CB)，已经发现了一系列广泛的神经递质和神经调节剂。它们主要由I型细胞产生和释放，作用于位于传入神经纤维、I型和II型细胞中的多种不同的亲离子和代谢性受体。大多数代谢性受体是G蛋白偶联受体(GPCRs)。在其他转基因或天然细胞中，GPCRs已被证明通过形成同/异复合体(二聚体或受体嵌合体)来建立物理受体-受体相互作用(RRI)，形成动态的单体/寡聚体平衡。RRIs调节配体结合、信号传递和GPCR前体的内化，它们被认为与神经系统的生理学、药理学和病理学有关。我们假设RRI也可能发生在CB的不同结构元素(I型细胞、II型细胞和传入纤维)中，这可能与化学接收、神经调节和组织可塑性有关。这一“工作假说”得到了文献数据的支持，这些文献数据报道了GPCRs在I型细胞、II型细胞或传入终末同时表达，这些GPCRs能够彼此物理地相互作用，形成同/异-复合体。关于不同神经递质/神经调节剂之间在CB中的相互作用的功能数据也支持这一假说。根据上述发现，在CB中可以推测的最重要的同/异复合体包括多巴胺、腺苷、ATP、阿片、组胺、5-羟色胺、内皮素、甘丙素、GABA、大麻素、血管紧张素、神经降压素和褪黑素的受体。从方法学的角度来看，未来的研究将通过生物物理方法(即生物发光/荧光共振能量转移、蛋白质片段互补分析、全内反射荧光显微镜、荧光相关光谱和光活化定位显微镜、X射线结晶学)或生化方法(免疫共沉淀、原位邻近连接分析)，证明上述受体在近距离(小于10 nm)内共定位。此外，功能方法将能够显示配体与一个受体结合是否会导致另一个受体(S)的生化特征(配体识别、解码和转运过程)的变化。可塑性方面也会引起人们的兴趣，因为发育和环境刺激(慢性、持续或间歇性低氧)会导致某些受体的表达发生变化，这可能会导致同/异复合体的单体/低聚物动态平衡及其相关的功能含义。
In the carotid body (CB), a wide series of neurotransmitters and neuromodulators have been identified. They are mainly produced and released by type I cells and act on many different ionotropic and metabotropic receptors located in afferent nerve fibers, type I and II cells. Most metabotropic receptors are G protein-coupled receptors (GPCRs). In other transfected or native cells, GPCRs have been demonstrated to establish physical receptor–receptor interactions (RRIs) with formation of homo/hetero-complexes (dimers or receptor mosaics) in a dynamic monomer/oligomer equilibrium. RRIs modulate ligand binding, signaling, and internalization of GPCR protomers and they are considered of relevance for physiology, pharmacology, and pathology of the nervous system. We hypothesize that RRI may also occur in the different structural elements of the CB (type I cells, type II cells, and afferent fibers), with potential implications in chemoreception, neuromodulation, and tissue plasticity. This ‘working hypothesis’ is supported by literature data reporting the contemporary expression, in type I cells, type II cells, or afferent terminals, of GPCRs which are able to physically interact with each other to form homo/hetero-complexes. Functional data about cross-talks in the CB between different neurotransmitters/neuromodulators also support the hypothesis. On the basis of the above findings, the most significant homo/hetero-complexes which could be postulated in the CB include receptors for dopamine, adenosine, ATP, opioids, histamine, serotonin, endothelin, galanin, GABA, cannabinoids, angiotensin, neurotensin, and melatonin. From a methodological point of view, future studies should demonstrate the colocalization in close proximity (less than 10 nm) of the above receptors, through biophysical (i.e., bioluminescence/fluorescence resonance energy transfer, protein-fragment complementation assay, total internal reflection fluorescence microscopy, fluorescence correlation spectroscopy and photoactivated localization microscopy, X-ray crystallography) or biochemical (co-immunoprecipitation, in situ proximity ligation assay) methods. Moreover, functional approaches will be able to show if ligand binding to one receptor produces changes in the biochemical characteristics (ligand recognition, decoding, and trafficking processes) of the other(s). Plasticity aspects would be also of interest, as development and environmental stimuli (chronic continuous or intermittent hypoxia) produce changes in the expression of certain receptors which could potentially invest the dynamic monomer/oligomer equilibrium of homo/hetero-complexes and the correlated functional implications.
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