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    • G has been shown to participate in various MT dependent

    2022-12-02

    Gβγ has been shown to participate in various MT-dependent processes such as cell growth and differentiation [15,[21], [22], [23], [24], [25], [26]]. G-protein β-subunit anti-sense oligonucleotides have been shown to inhibit cell proliferation and cause disorganization of the mitotic spindle in mammalian cells [21]. Genetic analyses in C. elegans, Drosophila, and mammalian cells have revealed that G-protein subunits (α and βγ) are involved in both cell polarity and cell division by positioning the mitotic spindle and attaching microtubules to the cell cortex [[22], [23], [24]]. The involvement of Gβγ in neuronal development and differentiation has been previously shown [25,26]. More recently, we have demonstrated that Gβγ-MT interactions and modulation of MT assembly is critical for NGF-induced neuronal differentiation of PC12 cells [15]. Overexpression of Gβγ in PC12 cells induced neurite outgrowth in the absence of NGF, further supporting the critical role of Gβγ-MT interaction in neuronal differentiation [15]. Gβ1-deficient mice have been shown to have neural tube defects [27], and Gβ5-knockout mice have been shown to display abnormal behavior and develop multiple Esomeprazole Sodium abnormalities [28]. The results presented here provide a mechanism by which GPCRs regulate various MT-dependent events by mobilizing Gβγ to bind to MTs and stimulate MT assembly and/or stabilization of MTs. In general, the wide variety of biological functions exerted by MTs (including chromosome movement in cell division, cell differentiation, organelle transport, and the maintenance of cell morphology) is based on the ability of tubulin to polymerize and depolymerize [reviewed in 29]. The data presented here point toward GPCRs as physiological regulators for MT assembly and dynamics. Regulation of MT assembly by Gβγ in response to activation of GPCRs may provide an alternative pathway by which GPCRs function in cellular signaling.
    Conflicts of interest
    Acknowledgments This work was supported by grant G12MD007592 (NIMHD, NIH) awarded to the Border Biomedical Research Center (BBRC) at the University of Texas at El Paso. This grant includes support for the BBRC Biomolecule Analysis, Genomic Analysis, and Cytometry Screening and Imaging Core Facilities.
    Introduction β-adrenergic receptor (βAR) signaling regulates a large repertoire of functions throughout the body, including cardiac contractility, vascular relaxation, immune cell function and central effects [1], [2], [3]. βAR desensitization has long been recognized as a contributing factor to the progression of various disease states and is largely mediated via regulation by G protein-coupled receptor kinase (GRK)-dependent processes [4], [5]. Upon βAR stimulation, GRK-dependent phosphorylation of the C-terminus of the receptor increases the recruitment of βarrestins (βarr), multifunctional scaffolding proteins that sterically interdict the association between βAR and active G proteins, as well as engage receptor internalization, mechanisms that act to arrest G protein-dependent βAR signaling and desensitize the receptor to prolonged stimulation. Since these classical desensitization mechanisms have been shown to lead to dysfunctional βAR signaling over time, contributing to maladaptive remodeling during heart failure in particular, the development of small molecule inhibitors of GRKs for the study of these processes and as potential therapeutics has been at the forefront of recent research efforts [6]. Via structural and biochemical analyses, the selective serotonin reuptake inhibitor (SSRI) paroxetine was recently identified as a GRK2 inhibitor, whereas its potency for inhibition of other GRK family members was shown to be much weaker [7]. Functionally, paroxetine was demonstrated to enhance βAR-dependent cardiomyocyte and cardiac contractility, as well as reverse cardiac dysfunction and myocardial βAR expression in mouse models of heart failure, while another SSRI that lacks GRK inhibitory capacity (fluoxetine) did not [7], [8]. These results are consistent with reduced βAR desensitization in response to GRK2 inhibition and highlighted the applicability of paroxetine for studying the impact of GRK2 inhibition in functional cells and in vivo models. However, despite these functional outcomes the proximal βAR signaling mechanisms sensitive to paroxetine have not been reported. Therefore, in this study we aimed to determine whether paroxetine indeed prevents GRK-dependent βAR signaling processes, including βAR phosphorylation, βarr recruitment and receptor internalization.