The life and times of endogenous opioid peptides: Updated understanding of synthesis, spatiotemporal dynamics, and the clinical impact in alcohol use disorder

Margolis, Elyssa B.; Moulton, Madelyn G; Lambeth, Philip S.; O’Meara, Matthew J.

doi:10.1016/j.neuropharm.2022.109376

Cited by 8 publications

(2 citation statements)

References 347 publications

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“…4D). The key interactions are in the central region of the peptide: during design, we excluded the N-terminal YGGF sequence which is shared between dynorphin A and B and other neuropeptides 32 , aiming to distinguish closely related peptides in the family where antibodies often fail, and the C-terminal region (-WDNQ) which is missing in some species (Fig. 4E).…”

Section: Structural Validationmentioning

confidence: 99%

Sequence-specific targeting of intrinsically disordered protein regions

Wu,

Jiang,

Hicks

et al. 2024

Preprint

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A general approach to design proteins that bind tightly and specifically to intrinsically disordered regions (IDRs) of proteins and flexible peptides would have wide application in biological research, therapeutics, and diagnosis. However, the lack of defined structures and the high variability in sequence and conformational preferences has complicated such efforts. We sought to develop a method combining biophysical principles with deep learning to readily generate binders for any disordered sequence. Instead of assuming a fixed regular structure for the target, general recognition is achieved by threading the query sequence through diverse extended binding modes in hundreds of templates with varying pocket depths and spacings, followed by RFdiffusion refinement to optimize the binder-target fit. We tested the method by designing binders to 39 highly diverse unstructured targets. Experimental testing of ∼36 designs per target yielded binders with affinities better than 100 nM in 34 cases, and in the pM range in four cases. The co-crystal structure of a designed binder in complex with dynorphin A is closely consistent with the design model. All by all binding experiments for 20 designs binding diverse targets show they are highly specific for the intended targets, with no crosstalk even for the closely related dynorphin A and dynorphin B. Our approach thus could provide a general solution to the intrinsically disordered protein and peptide recognition problem.

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Section: Structural Validationmentioning

confidence: 99%

Sequence-specific targeting of intrinsically disordered protein regions

Wu,

Jiang,

Hicks

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…There is a strong precedent for the importance of opioid signaling in the striatum, with extensive literature pointing to numerous striatal functions of other endogenous opioid systems, most notably mu and kappa, in the coordination of key reward and feeding behaviors ((Bodnar et al 1995, Ragnauth et al 2000, Castro and Berridge 2014, Castro and Bruchas 2019, Castro et al 2021). In addition, dysregulated striatal opioid signaling can contribute to a wide range of neurological disorders including mood disorders, substance use disorder, Huntington’s disease, Parkinson’s disease, and schizophrenia among others (Sgroi and Tonini 2018, Cui et al 2014b, Banghart et al 2015, Margolis et al 2023, Morigaki et al 2020, Kennedy et al 2006, Canales and Graybiel 2000, Clark and Abi-Dargham 2019), in part owing to the distinct patterns of expression exhibited by different opioid receptors and peptides throughout striatum, including differential expression in striosome and matrix compartments (Crittenden and Graybiel 2011, Graybiel 1990, Brimblecombe and Cragg 2017, Tajima and Fukuda 2013). Although Pnoc -expressing neurons can be found throughout the striatum, their organization within striatal neuronal types and their anatomical intersection with dopamine circuitry across striatal subregions have remained largely unknown, especially in comparison to the other striatal opioid systems.…”

Section: Introductionmentioning

confidence: 99%

Developmental and adult striatal patterning of nociceptin ligand marks striosomal population with direct dopamine projections

Hueske,

Stine,

Yoshida

et al. 2024

Preprint

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Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high-resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin-Cre reporter mouse line, we characterized highly selective striosomal patterning ofPnocmRNA expression in mouse dorsal striatum, reflecting early developmental expression ofPnoc. In the ventral striatum,Pnocexpression was clustered across the nucleus accumbens core and medial shell, including in adult striatum. We found that PnoctdTomatoreporter cells largely comprise a population of dopamine receptor D1 (Drd1) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projections neurons for their direct innervation of midbrain dopamine neurons. These findings provide new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striato-nigral circuits.

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Developmental and Adult Striatal Patterning of Nociceptin Ligand Marks Striosomal Population With Direct Dopamine Projections

Hueske,

Stine,

Yoshida

et al. 2024

J of Comparative Neurology

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Circuit influences on the midbrain dopamine system are crucial to adaptive behavior and cognition. Recent developments in the study of neuropeptide systems have enabled high‐resolution investigations of the intersection of neuromodulatory signals with basal ganglia circuitry, identifying the nociceptin/orphanin FQ (N/OFQ) endogenous opioid peptide system as a prospective regulator of striatal dopamine signaling. Using a prepronociceptin‐Cre reporter mouse line, we characterized highly selective striosomal patterning of Pnoc mRNA expression in mouse dorsal striatum, reflecting the early developmental expression of Pnoc. In the ventral striatum, Pnoc expression in the nucleus accumbens core was grouped in clusters akin to the distribution found in striosomes. We found that PnoctdTomato reporter cells largely comprise a population of dopamine receptor D1 (Drd1) expressing medium spiny projection neurons localized in dorsal striosomes, known to be unique among striatal projection neurons for their direct innervation of midbrain dopamine neurons. These findings provide a new understanding of the intersection of the N/OFQ system among basal ganglia circuits with particular implications for developmental regulation or wiring of striato‐nigral circuits.

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The life and times of endogenous opioid peptides: Updated understanding of synthesis, spatiotemporal dynamics, and the clinical impact in alcohol use disorder

Cited by 8 publications

References 347 publications

Sequence-specific targeting of intrinsically disordered protein regions

Sequence-specific targeting of intrinsically disordered protein regions

Developmental and adult striatal patterning of nociceptin ligand marks striosomal population with direct dopamine projections

Developmental and Adult Striatal Patterning of Nociceptin Ligand Marks Striosomal Population With Direct Dopamine Projections

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