Genetic deletion ofRgs12in mice affects serotonin transporter expression and functionin vivoandex vivo

White, Allison N; Gross, Joshua; Kaski, Shane W; Trexler, Kristen R.; Wix, Kim; Wetsel, William C.; Kinsey, Steven G.; Siderovski, David P.; Setola, Vincent

doi:10.1177/0269881120944160

Cited by 2 publications

(1 citation statement)

References 76 publications

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“…In addition, we noted two missense mutations across two patients in RGS12 (p.Gly454Asp, p.Arg403Cys) and NAV1 (p.Pro1507Ser, p.Arg1581Cys) . RGS12 was shown to be a critical modulator of serotonergic neurotransmission (43), while NAV1 is a relatively understudied gene that is involved in neuronal development and regeneration (44).…”

Section: Resultsmentioning

confidence: 99%

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis

Rajeh,

Cornman,

Gupta

et al. 2023

Preprint

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Prurigo nodularis (PN) is a chronic inflammatory skin disease that disproportionately affects African Americans and is characterized by pruritic skin nodules of unknown etiology. Little is known about genetic alterations in PN pathogenesis, especially relating to somatic events which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 PN patients and 10 atopic dermatitis (AD) patients for comparison. Somatic mutational analysis revealed that PN lesional skin harbors pervasive somatic mutations in fibrotic, neurotropic, and cancer-associated genes. Nonsynonymous mutations were most frequent inNOTCH1and the Notch signaling pathway, a regulator of cellular proliferation and tissue fibrosis, andNOTCH1mutations were absent in AD. Somatic copy-number analysis, combined with expression data, showed that recurrently deleted and downregulated genes in PN lesional skin are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increasedNOTCH1expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, multi-center data revealed a significantly increased risk ofNOTCH1-associated diseases in PN patients. In characterizing the somatic landscape of PN, we uncover novel insights into its pathophysiology and identify a role for dysregulated Notch signaling in PN.

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Section: Resultsmentioning

confidence: 99%

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis

Rajeh,

Cornman,

Gupta

et al. 2023

Preprint

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Potential for Kappa-Opioid Receptor Agonists to Engineer Nonaddictive Analgesics: A Narrative Review

Kaski

White

Gross

et al. 2020

Anesthesia &Amp; Analgesia

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A serious adverse effect of prescription opioid analgesics is addiction, both to these analgesics and to illicit drugs like heroin that also activate the µ-opioid receptor (MOR). Opioid use disorder (OUD) and opioid overdose deaths represent a current American health crisis, and the prescription of opioid analgesics has contributed significantly to this crisis. While prescription opioids are highly effective analgesics, there currently exists no facile way to use them for extended periods without the risk of addiction. If addiction caused by MOR-targeting analgesics could be blocked by blending in a new “antiaddiction” ingredient that does not diminish analgesia and does not introduce its own therapeutically limiting side effects, then continued clinical use of prescription opioids for treating pain could be maintained (or even enhanced) instead of curtailed. In this narrative review, we contextualize this hypothesis, first with a brief overview of the current American opioid addiction crisis. The neurobiology of 2 key receptors in OUD development, MOR and the κ-opioid receptor (KOR), is then discussed to highlight the neuroanatomical features and circuitry in which signal transduction from these receptors lie in opposition—creating opportunities for pharmacological intervention in curtailing the addictive potential of MOR agonism. Prior findings with mixed MOR/KOR agonists are considered before exploring new potential avenues such as biased KOR agonists. New preclinical data are highlighted, demonstrating that the G protein–biased KOR agonist nalfurafine reduces the rewarding properties of MOR-targeting analgesics and enhances MOR-targeting analgesic-induced antinociception. Finally, we discuss the recent discovery that a regulator of G protein signaling (namely, RGS12) is a key component of signaling bias at KOR, presenting another drug discovery target toward identifying a single agent or adjuvant to be added to traditional opioid analgesics that could reduce or eliminate the addictive potential of the latter drug.

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Genetic deletion ofRgs12in mice affects serotonin transporter expression and functionin vivoandex vivo

Cited by 2 publications

References 76 publications

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis

Potential for Kappa-Opioid Receptor Agonists to Engineer Nonaddictive Analgesics: A Narrative Review

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