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• W4200230632 abstract "Activation of a specific protein kinase C (PKC) isoform during stimulation of Gq protein-coupled receptors (GqPCRs) is determined by homologous receptor desensitization that controls the spatiotemporal formation of downstream Gq signalling molecules. Furthermore, GqPCR-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 α1B-adrenergic receptor (α1B-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 α1B-ARs and α1B-ARs lacking PKC or GRK2 phosphorylation sites (Δ391-401, α1B-ΔPKC-AR and Δ402-520, α1B-ΔGRK-AR) by means of FRET-based biosensors in HEK293 that served as online-assays of receptor activity. K+ currents through KCNQ1/KCNE1 channels (IKs), which are regulated by both phosphatidylinositol 4,5-bisphosphate (PIP2)-depletion and/or phosphorylation by PKC, were measured as a functional readout of wildtype and mutant α1B-AR receptor activity. As a novel finding, we provide evidence that deletion of PKC and GRK2 phosphorylation sites in α1B-ARs abrogates the contribution of PKCα to homologous receptor desensitization. Instead, the time course of mutant receptor activity was specifically modulated by PKCβ. Mutant α1B-ARs displayed pronounced homologous receptor desensitization that was abolished by PKCβ-specific pharmacological inhibitors. IKs modulation during stimulation of wildtype and mutant α1B-ARs displayed transient inhibition and current facilitation after agonist withdrawal with reduced capability of mutant α1B-ARs to induce IKs inhibition. Pharmacological inhibition of the PKCβ isoform did not augment IKs reduction by mutant α1B-ARs, but shifted IKs modulation towards current facilitation. Coexpression of an inactive (dominant-negative) PKCδ isoform (DN-PKCδ) abolished IKs facilitation in α1B-ΔGRK-AR-expressing cells, but not in α1B-ΔPKC-AR-expressing cells. The data indicate that the differential modulation of IKs activity by α1B-ΔGRK- and α1B-ΔPKC-receptors is attributed to the activation of entirely distinct novel PKC isoforms. To summarize, specific phosphorylation sites within the wildtype and mutant α1B-adrenergic receptors are targeted by different PKC isoforms, resulting in differential regulation of receptor desensitization and effector function." @default.
• W4200230632 created "2021-12-31" @default.
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• W4200230632 date "2022-03-01" @default.
• W4200230632 modified "2023-09-25" @default.
• W4200230632 title "PKC-isoform specific regulation of receptor desensitization and KCNQ1/KCNE1 K+ channel activity by mutant α1B-adrenergic receptors" @default.
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• W4200230632 doi "https://doi.org/10.1016/j.cellsig.2021.110228" @default.
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