PharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells

Susanne Prokop, Péter Ábrányi-Balogh, Benjámin Barti, Márton Vámosi, Miklós Zöldi, László Barna, Gabriella M. Urbán, András Dávid Tóth, Barna Dudok, Attila Egyed, Hui Deng, Gian Marco Leggio, László Hunyady, Mario van der Stelt, György M. Keserű and István Katona ()
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Susanne Prokop: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine
Péter Ábrányi-Balogh: Medicinal Chemistry Research Group, Research Centre for Natural Sciences
Benjámin Barti: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine
Márton Vámosi: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine
Miklós Zöldi: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine
László Barna: Nikon Center of Excellence for Neuronal Imaging, Institute of Experimental Medicine
Gabriella M. Urbán: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine
András Dávid Tóth: Semmelweis University
Barna Dudok: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine
Attila Egyed: Medicinal Chemistry Research Group, Research Centre for Natural Sciences
Hui Deng: Leiden University & Oncode Institute
Gian Marco Leggio: University of Catania
László Hunyady: Semmelweis University
Mario van der Stelt: Leiden University & Oncode Institute
György M. Keserű: Medicinal Chemistry Research Group, Research Centre for Natural Sciences
István Katona: Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26757-z

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