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The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production—particularly IL-4/13—are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Activation of a specific protein kinase C (PKC) isoform during stimulation of G q protein-coupled receptors (G q PCRs) is determined by homologous receptor desensitization that controls the spatiotemporal formation of downstream G q signalling molecules. Furthermore, G q PCR-activated PKC isoforms specifically regulate receptor activity via a negative feedback mechanism. In the present study, we investigated the contribution of several phosphorylation sites in the α 1B -adrenergic receptor (α 1B -AR) for PKC and G protein coupled receptor kinase 2 (GRK2) to homologous receptor desensitization and effector modulation. We analyzed signalling events downstream to human wildtype α 1B -ARs and α 1B -ARs lacking PKC or GRK2 phosphorylation sites (Δ391–401, α 1B -ΔPKC-AR and Δ402–520, α 1B -ΔGRK-AR) by means of FRET-based biosensors in HEK293 that served as online-assays of receptor activity. K+ currents through KCNQ1/KCNE1 channels (I Ks), which are regulated by both phosphatidylinositol 4,5-bisphosphate (PIP 2)-depletion and/or phosphorylation by PKC, were measured as a functional readout of wildtype and mutant α 1B -AR receptor activity. As a novel finding, we provide evidence that deletion of PKC and GRK2 phosphorylation sites in α 1B -ARs abrogates the contribution of PKCα to homologous receptor desensitization. Instead, the time course of mutant receptor activity was specifically modulated by PKCβ. Mutant α 1B -ARs displayed pronounced homologous receptor desensitization that was abolished by PKCβ-specific pharmacological inhibitors. I Ks modulation during stimulation of wildtype and mutant α 1B -ARs displayed transient inhibition and current facilitation after agonist withdrawal with reduced capability of mutant α 1B -ARs to induce I Ks inhibition. Pharmacological inhibition of the PKCβ isoform did not augment I Ks reduction by mutant α 1B -ARs, but shifted I Ks modulation towards current facilitation. Coexpression of an inactive (dominant-negative) PKCδ isoform (DN-PKCδ) abolished I Ks facilitation in α 1B -ΔGRK-AR-expressing cells, but not in α 1B -ΔPKC-AR-expressing cells. The data indicate that the differential modulation of I Ks activity by α 1B -ΔGRK- and α 1B -ΔPKC-receptors is attributed to the activation of entirely distinct novel PKC isoforms. To summarize, specific phosphorylation sites within the wildtype and mutant α 1B -adrenergic receptors are targeted by different PKC isoforms, resulting in differential regulation of receptor desensitization and effector function. • PKCα-induced regulation of receptor activity is abolished in mutant α 1B -ARs. • Homologous desensitization of mutant α 1B -ARs is specifically regulated by PKCβ. • Inhibition of PKCβ enhances I Ks facilitation induced by mutant α 1B -ARs. • I Ks facilitation is attributed to novel PKC activation. [ABSTRACT FROM AUTHOR]