Integrative and Systems Biology, Faculty of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow, UK.
Br J Pharmacol. 2010 Feb;159(4):787-96. doi: 10.1111/j.1476-5381.2009.00608.x. Epub 2010 Feb 5.
Pharmacological analysis of synergism or functional antagonism between different receptors commonly assumes that interacting receptors are located in the same cells. We have now investigated the distribution of alpha-adrenoceptors, beta-adrenoceptors and cannabinoid-like (GPR55) receptors in the mouse arteries.
Fluorescence intensity from vascular tissue incubated with fluorescent ligands (alpha(1)-adrenoceptor ligand, BODIPY-FL-prazosin, QAPB; beta-adrenoceptor ligand, TMR-CGP12177; fluorescent angiotensin II; a novel diarylpyrazole cannabinoid ligand (Tocrifluor 1117, T1117) was measured with confocal microscopy. Small mesenteric and tail arteries of wild-type and alpha(1B/D)-adrenoceptor-KO mice were used.
T1117, a fluorescent form of the cannabinoid CB(1) receptor antagonist AM251, was a ligand for GPR55, with low affinity for CB(1) receptors. In mesenteric arterial smooth muscle cells, alpha(1A)-adrenoceptors were predominantly located in different cells from those with beta-adrenoceptors, angiotensin receptors or cannabinoid-like (GPR55) receptors. Cells with beta-adrenoceptors predominated at arterial branches. Endothelial cells expressed beta-adrenoceptors, alpha-adrenoceptors and cannabinoid-like receptors. Only endothelial alpha-adrenoceptors appeared in clusters. Adventitia was a rich source of G protein-coupled receptors (GPCRs), particularly fibroblasts and nerve tracts, where Schwann cells bound alpha-adrenoceptor, beta-adrenoceptor and CB-receptor ligands, with a mix of separate receptor locations and co-localization.
Within each cell type, each GPCR had a distinctive heterogeneous distribution with limited co-localization, providing a guide to the possibilities for functional synergism, and suggesting a new paradigm for synergism in which interactions may be either between cells or involve converging intracellular signalling processes.
不同受体之间协同作用或功能拮抗的药理学分析通常假定相互作用的受体位于同一细胞中。我们现在研究了小鼠动脉中α-肾上腺素能受体、β-肾上腺素能受体和大麻素样（GPR55）受体的分布。
用荧光配体（α（1）-肾上腺素能受体配体，BODIPY-FL-哌唑嗪，QAPB；β-肾上腺素能受体配体，TMR-CGP12177；荧光血管紧张素 II；新型二芳基吡唑类大麻素配体（Tocrifluor 1117，T1117）孵育血管组织的荧光强度用共聚焦显微镜测量。使用野生型和α（1B/D）-肾上腺素能受体-KO 小鼠的肠系膜和尾动脉。
T1117 是大麻素 CB1 受体拮抗剂 AM251 的荧光形式，是 GPR55 的配体，对 CB1 受体的亲和力低。在肠系膜动脉平滑肌细胞中，α（1A）-肾上腺素能受体主要位于与β-肾上腺素能受体、血管紧张素受体或大麻素样（GPR55）受体不同的细胞中。β-肾上腺素能受体占优势的细胞位于动脉分支处。内皮细胞表达β-肾上腺素能受体、α-肾上腺素能受体和大麻素样受体。只有内皮细胞的α-肾上腺素能受体出现在簇中。外膜是 G 蛋白偶联受体（GPCRs）的丰富来源，特别是成纤维细胞和神经束，其中施万细胞结合α-肾上腺素能受体、β-肾上腺素能受体和 CB 受体配体，具有单独受体位置和共定位的混合。
在每种细胞类型中，每种 GPCR 都具有独特的异质分布，且共定位有限，为功能协同作用的可能性提供了指导，并提出了一种新的协同作用范例，其中相互作用可能发生在细胞之间，也可能涉及收敛的细胞内信号转导过程。
