Caged-carvedilol as a new tool for visible-light photopharmacology of β-adrenoceptors in native tissues

Duran-Corbera, Anna; Font, Joan Nogué i; Faria, Melissa; Prats, Eva; Consegal, Marta; Catena, Juanlo; Muñoz, Lourdes; Raldúa, Demetrio; Rodríguez‐Sinovas, Antonio; Llebaría, Amadeu; Rovira, Xavier

doi:10.1016/j.isci.2022.105128

Cited by 6 publications

(2 citation statements)

References 73 publications

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“…Other approaches to manipulate intracellular GPCR signaling take advantage of chemically modified agonists and antagonists that are inactive until light-induced uncaging of active ligands [44][45][46][47][48] . While this approach has been used to temporally control GPCR activity, spatial control has mainly been applied to map synaptic connectivity in neuronal networks 47 .…”

Section: Discussionmentioning

confidence: 99%

Selective activation of intracellular β1AR using a spatially restricted antagonist

Liccardo,

Morstein,

Lin

et al. 2023

Preprint

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G-protein-coupled receptors (GPCRs) regulate several physiological and pathological processes and represent the target of approximately 30% of FDA-approved drugs. GPCR-mediated signaling was thought to occur exclusively at the plasma membrane. However, recent studies have unveiled their presence and function at subcellular membrane compartments. There is a growing interest in studying compartmentalized signaling of GPCRs. This requires development of novel tools to separate GPCRs signaling at the plasma membrane from the ones initiated at intracellular compartments. We took advantage of the structural and pharmacological information available for β1-adrenergic receptor (β1AR), an exemplary GPCR that functions at subcellular compartments, and rationally designed spatially restricted antagonists. We generated a cell impermeable β1AR antagonist by conjugating a suitable pharmacophore to a sulfonate-containing fluorophore. This cell-impermeable antagonist only inhibited β1AR on the plasma membrane. In contrast, a cell permeable β1AR agonist containing a non-sulfonated fluorophore, efficiently inhibited both the plasma membrane and Golgi pools of β1ARs. Furthermore, the cell impermeable antagonist selectively inhibited the phosphorylation of downstream effectors of PKA proximal to the plasma membrane in adult cardiomyocytes while β1AR intracellular pool remained active. Our tools offer promising avenues for investigating compartmentalized β1AR signaling in various context, potentially advancing our understanding of β1AR-mediated cellular responses in health and disease. They also offer a general strategy to study compartmentalized signaling for other GPCRs in various biological systems.

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Section: Discussionmentioning

confidence: 99%

Selective activation of intracellular β1AR using a spatially restricted antagonist

Liccardo,

Morstein,

Lin

et al. 2023

Preprint

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“…To achieve optical control of channel activity, azobenzenes were coupled to selective ion channel blockers covalently conjugated to the channel proteins [ 146 , 147 ]. Transfering this approach to GPCR modulation, the irreversible photoswitch caged-carvedilol [ 89 ] and the reversible, para-substituted azobenzenes, named parazolol-1 (pAzo-1) and parazolol-2, which specifically target the β1-AR [ 88 ] (Fig. 3 ), were applied to cultured cardiomyocytes, murine-isolated perfused hearts, and living zebrafish larvae.…”

Section: Optogeneticsmentioning

confidence: 99%

Cardiac optogenetics: shining light on signaling pathways

Leemann,

Schneider-Warme,

Kleinlogel

2023

Pflugers Arch - Eur J Physiol

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In the early 2000s, the field of neuroscience experienced a groundbreaking transformation with the advent of optogenetics. This innovative technique harnesses the properties of naturally occurring and genetically engineered rhodopsins to confer light sensitivity upon target cells. The remarkable spatiotemporal precision offered by optogenetics has provided researchers with unprecedented opportunities to dissect cellular physiology, leading to an entirely new level of investigation. Initially revolutionizing neuroscience, optogenetics quickly piqued the interest of the wider scientific community, and optogenetic applications were expanded to cardiovascular research. Over the past decade, researchers have employed various optical tools to observe, regulate, and steer the membrane potential of excitable cells in the heart. Despite these advancements, achieving control over specific signaling pathways within the heart has remained an elusive goal. Here, we review the optogenetic tools suitable to control cardiac signaling pathways with a focus on GPCR signaling, and delineate potential applications for studying these pathways, both in healthy and diseased hearts. By shedding light on these exciting developments, we hope to contribute to the ongoing progress in basic cardiac research to facilitate the discovery of novel therapeutic possibilities for treating cardiovascular pathologies.

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Coumarin‐Derived Caging Groups in the Spotlight: Tailoring Physiochemical and Photophysical Properties

Clotworthy,

Dawson,

Johnstone

et al. 2024

ChemPlusChem

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The development of light‐responsive molecular tools enables spatiotemporal control of biochemical processes with superior precision. Amongst these molecular tools, photolabile caging groups are employed to prevent critical binding interactions between a bioactive molecule and its corresponding target. Only upon irradiation with light, the bioactive is released in its ‘active’ form and is now readily available to bind to its target. Coumarin‐derived caging groups constitute one of the most popular classes of photolabile protecting groups, due to their facile synthetic accessibility, ease of tuning photophysical properties via structural modification and rapid photolysis reactions. Herein, we highlight the recent progress made on the development of coumarin‐derived caging groups, in which the red‐shifting of absorption spectra, improving aqueous solubility and tailoring sub‐cellular localisation has been of particular interest.

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Caged-carvedilol as a new tool for visible-light photopharmacology of β-adrenoceptors in native tissues

Cited by 6 publications

References 73 publications

Selective activation of intracellular β1AR using a spatially restricted antagonist

Selective activation of intracellular β1AR using a spatially restricted antagonist

Cardiac optogenetics: shining light on signaling pathways

Coumarin‐Derived Caging Groups in the Spotlight: Tailoring Physiochemical and Photophysical Properties

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