PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells.
PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells.
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DOI：
10.1038/s41467-021-26757-z
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发表时间：
2021-11-11
影响因子：
16.6
通讯作者：
Katona I
中科院分区：
文献类型：
--
作者：
Prokop S;Ábrányi-Balogh P;Barti B;Vámosi M;Zöldi M;Barna L;Urbán GM;Tóth AD;Dudok B;Egyed A;Deng H;Leggio GM;Hunyady L;van der Stelt M;Keserű GM;Katona I
传统上，免疫标记和放射自显影被用作可视化和收集生理和病理过程分子信息的首选方法。在这里，我们介绍了PharmacoSTORM超分辨率成像，它结合了这些方法的互补优势，并实现了细胞类型和室特异性的纳米级分子测量。我们对荧光团标记的高亲和力受体配体和酶抑制剂进行了合理的化学设计；并证明了PharmacoSTORM对三种蛋白质类别和临床批准的抗精神病和抗抑郁药物卡吡嗪的广泛适用性。由于卡吡嗪的神经生物学底物仍然难以捉摸，我们利用PharmacoSTORM提供了体内证据，证明卡吡嗪主要结合Calleja颗粒细胞轴突上的D3多巴胺受体，但避免多巴胺能末端。这些发现表明，PharmacoSTORM有助于在纳米水平上以细胞类型和亚细胞环境依赖的方式以及在复杂的组织制剂中量化药物靶标相互作用位点。此外，研究结果强调了被低估的Calleja岛在前脑腹侧的神经精神意义。作者介绍了利用荧光配体和免疫标记进行细胞和亚细胞纳米级分子药理学的PharmacoSTORM单分子成像技术。他们通过可视化卡吡嗪与Calleja颗粒细胞轴突上D3多巴胺受体的结合来证明其能力。
Immunolabeling and autoradiography have traditionally been applied as the methods-of-choice to visualize and collect molecular information about physiological and pathological processes. Here, we introduce PharmacoSTORM super-resolution imaging that combines the complementary advantages of these approaches and enables cell-type- and compartment-specific nanoscale molecular measurements. We exploited rational chemical design for fluorophore-tagged high-affinity receptor ligands and an enzyme inhibitor; and demonstrated broad PharmacoSTORM applicability for three protein classes and for cariprazine, a clinically approved antipsychotic and antidepressant drug. Because the neurobiological substrate of cariprazine has remained elusive, we took advantage of PharmacoSTORM to provide in vivo evidence that cariprazine predominantly binds to D3 dopamine receptors on Islands of Calleja granule cell axons but avoids dopaminergic terminals. These findings show that PharmacoSTORM helps to quantify drug-target interaction sites at the nanoscale level in a cell-type- and subcellular context-dependent manner and within complex tissue preparations. Moreover, the results highlight the underappreciated neuropsychiatric significance of the Islands of Calleja in the ventral forebrain. The authors introduce PharmacoSTORM single-molecule imaging that uses fluorescent ligands and immunolabeling for cellular and subcellular nanoscale molecular pharmacology. They demonstrate its capabilities by visualizing cariprazine binding to D3 dopamine receptors on Islands of Calleja granule cell axons.
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影响因子：
16.2
作者：
Dani, Adish;Huang, Bo;Bergan, Joseph;Dulac, Catherine;Zhuang, Xiaowei
通讯作者：
Zhuang, Xiaowei
影响因子：
2.3
作者：
Fricke, Franziska;Malkusch, Sebastian;Heilemann, Mike
通讯作者：
Heilemann, Mike
影响因子：
56.9
作者：
Bates, Mark;Huang, Bo;Zhuang, Xiaowei
通讯作者：
Zhuang, Xiaowei
影响因子：
2.5
作者：
FALLON, JH;RILEY, JN;MOORE, RY
通讯作者：
MOORE, RY
影响因子：
7.3
作者：
Daly, C. J.;Ross, R. A.;McGrath, J. C.
通讯作者：
McGrath, J. C.