In vivo photopharmacology with a caged mu opioid receptor agonist drives rapid changes in behavior

Ma, Xiang; Johnson, Desiree A; He, Xinyi Jenny; Layden, Aryanna E; McClain, Shannan P; Yung, Jean C.; Rizzo, Arianna; Bonaventura, Jordi; Banghart, Matthew R.

doi:10.1038/s41592-023-01819-w

Cited by 20 publications

(12 citation statements)

References 28 publications

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“…, in the receptor-expressing neuron) and the presynaptic, peptide-releasing cell. Moving in vivo , caged neuropeptides offer the ability to isolate the effects of time-resolved peptide signaling on neuronal activity and behavior . The ability to rapidly generate useful photopharmacology tools for neuropeptidergic systems will accelerate our understanding of neuropeptide signaling in the nervous system, which is currently an area of intense focus in neuroscience research …”

Section: Discussionmentioning

confidence: 99%

A Biomimetic C-Terminal Extension Strategy for Photocaging Amidated Neuropeptides

Layden,

Ma,

Johnson

et al. 2023

J. Am. Chem. Soc.

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Photoactivatable neuropeptides offer a robust stimulus–response relationship that can drive mechanistic studies into the physiological mechanisms of neuropeptidergic transmission. The majority of neuropeptides contain a C-terminal amide, which offers a potentially general site for installation of a C-terminal caging group. Here, we report a biomimetic caging strategy in which the neuropeptide C-terminus is extended via a photocleavable amino acid to mimic the proneuropeptides found in large dense-core vesicles. We explored this approach with four prominent neuropeptides: gastrin-releasing peptide (GRP), oxytocin (OT), substance P (SP), and cholecystokinin (CCK). C-terminus extension greatly reduced the activity of all four peptides at heterologously expressed receptors. In cell type-specific electrophysiological recordings from acute brain slices, subsecond flashes of ultraviolet light produced rapidly activating membrane currents via activation of endogenous G protein-coupled receptors. Subsequent mechanistic studies with caged CCK revealed a role for extracellular proteases in shaping the temporal dynamics of CCK signaling, and a striking switch-like, cell-autonomous anti-opioid effect of transient CCK signaling in hippocampal parvalbumin interneurons. These results suggest that C-terminus extension with a photocleavable linker may be a general strategy for photocaging amidated neuropeptides and demonstrate how photocaged neuropeptides can provide mechanistic insights into neuropeptide signaling that are inaccessible using conventional approaches.

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Section: Discussionmentioning

confidence: 99%

A Biomimetic C-Terminal Extension Strategy for Photocaging Amidated Neuropeptides

Layden,

Ma,

Johnson

et al. 2023

J. Am. Chem. Soc.

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“…Photopharmacology represents a powerful means of optically controlling biological function through the use of light-sensitive compounds 1,2 . In addition to its use in a wide variety of basic science applications [3][4][5][6][7][8][9][10][11][12] , photopharmacology has now entered clinical trials via KIO-301, a photoswitchable ion channel blocker with great potential for vision restoration 13 . This compound utilizes an azobenzene-based photoswitch, which represents one of the primary chemical moieties used in photopharmacological probes 14 .…”

Section: Main Textmentioning

confidence: 99%

Deuteration provides a general strategy to enhance azobenzene-based photopharmacology

Roßmann,

Gonzalez-Hernandez,

Bhuyan

et al. 2023

Preprint

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Herein, we present deuterated azobenzene photoswitches as a general means of enhancing photopharmacological molecules. Deuteration can improve azobenzene performance in terms of light sensitivity, photoswitch efficiency, and photoswitch kinetics with minimal alteration to the underlying structure of the photopharmacological ligand. We report synthesized deuterated azobenzene-based ligands for the optimized optical control of ion channel and G protein-coupled receptor function in live cells, setting the stage for the straightforward, widespread adoption of this approach.

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“…Photopharmacological approaches have recently been explored for pain modulation by members of our team ( 12–14 ) and by others ( 15, 16 ). The drug treatment of neuropathic pain, i.e., chronic pain originating from damage or disease of the somatosensory system, remains a major therapeutic challenge and unmet medical need because of severe side effects and a high percentage of patients resistant to medication ( 17, 18 ).…”

Section: Introductionmentioning

confidence: 99%

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

Notartomaso,

Antenucci,

Mazzitelli

et al. 2024

Preprint

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Knowing the site of drug action is important to optimize effectiveness and address any side effects. We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in in the prelimbic and infralimbic cortices, and thalamus. This demonstrates that mGlu5 receptor blockade in the medial prefrontal cortex and thalamus is both sufficient and necessary for the analgesic activity of mGlu5 receptor antagonists. Surprisingly, when light was delivered in the basolateral amygdala, local activation of systemic JF-NP-26 reduced pain thresholds, whereas inactivation of alloswitch-1 enhanced analgesia. Electrophysiological analysis showed that alloswitch-1 increased excitatory synaptic responses in prelimbic pyramidal neurons evoked by stimulation of BLA input, and decreased feedforward inhibition of amygdala output neurons by BLA. Both effects were reversed by optical silencing and reinstated by optical reactivation of alloswitch-1. These findings demonstrate for the first time that the action of mGlu5 receptors in the pain neuraxis is not homogenous, and suggest that blockade of mGlu5 receptors in the BLA may limit the overall analgesic activity of mGlu5 receptor antagonists. This could explain the suboptimal effect of mGlu5 NAMs on pain in human studies and validate photopharmacology as an important tool to determine ideal target sites for systemic drugs.

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In vivo photopharmacology with a caged mu opioid receptor agonist drives rapid changes in behavior

Cited by 20 publications

References 28 publications

A Biomimetic C-Terminal Extension Strategy for Photocaging Amidated Neuropeptides

A Biomimetic C-Terminal Extension Strategy for Photocaging Amidated Neuropeptides

Deuteration provides a general strategy to enhance azobenzene-based photopharmacology

A “double-edged” role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs

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