G protein-coupled receptor signalling in the cardiac nuclear membrane: evidence and possible roles in physiological and pathophysiological function. J Physiol

Department of Medicine, Université de Montréal, Montréal, Québec, Canada H3C 3J7.
The Journal of Physiology (Impact Factor: 5.04). 12/2011; 590(Pt 6):1313-30. DOI: 10.1113/jphysiol.2011.222794
Source: PubMed


G protein-coupled receptors (GPCRs) play key physiological roles in numerous tissues, including the heart, and their dysfunction influences a wide range of cardiovascular diseases. Recently, the notion of nuclear localization and action of GPCRs has become more widely accepted. Nuclear-localized receptors may regulate distinct signalling pathways, suggesting that the biological responses mediated by GPCRs are not solely initiated at the cell surface but may result from the integration of extracellular and intracellular signalling pathways. Many of the observed nuclear effects are not prevented by classical inhibitors that exclusively target cell surface receptors, presumably because of their structures, lipophilic properties, or affinity for nuclear receptors. In this topical review, we discuss specifically how angiotensin-II, endothelin, β-adrenergic and opioid receptors located on the nuclear envelope activate signalling pathways, which convert intracrine stimuli into acute responses such as generation of second messengers and direct genomic effects, and thereby participate in the development of cardiovascular disorders.

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Available from: Bruce Allen, Sep 03, 2014
    • "To date, most models consider the receptor to be located on cell surface membranes when ligand binding initiates signalling. However, numerous GPCRs have been shown to localize to intracellular membranes such as nuclear and mitochondrial membranes in different primary cell systems, including cardiac myocytes, endothelial cells, vascular smooth muscle cells, neurons, hepatocytes, and kidney cells [1] [2] [3]. Intracellular GPCR signalling adds yet more complexity and selectivity to the system, as (1) a GPCR located on an intracellular membrane may serve a role that is distinct from the same receptor located at the cell surface and (2) there may be be restrictions on which ligands can access its intracellular versus cell-surface receptor. "
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    ABSTRACT: In addition to cell surface membranes, numerous G protein-coupled receptors (GPCRs) are located on intracellular membranes including the nuclear envelope. Although the role of numerous GPCRs at the cell surface has been well characterized, the physiological function of these same receptors located on intracellular membranes remains to be determined. Here, we employ a novel caged Ang-II analog, cAng-II, to compare the effects of the activation of cell surface versus intracellular angiotensin receptors in intact cardiomyocytes. When added extracellularly to HEK 293 cells, Ang-II and photolysed cAng-II increased ERK1/2 phosphorylation (via AT1R) and cGMP production (AT2R). In contrast unphotolysed cAng-II did not. Cellular uptake of cAng-II was 6-fold greater than that of Ang-II and comparable to the HIV TAT(48-60) peptide. Intracellular photolysis of cAng-II induced an increase in nucleoplasmic Ca(2+) ([Ca(2+)]n) that was greater than that induced by extracellular application of Ang-II. We conclude that cell-permeable ligands that can access intracellular GPCRs may evoke responses distinct from those with access restricted to the same receptor located on the cell surface.
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    • "Intranuclear production of second messengers , including cAMP, IP3 and DAG is also well documented (reviewed in [2]). The nuclear GPCRs are thought to regulate cell proliferation and survival, DNA replication, transcription, inflammation and tumorigenesis [2] [3]. Vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) belong to a family of structurally related peptides including also secretin and glucagon. "
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    ABSTRACT: An increasing number of G protein-coupled receptors, like receptors for vasoactive intestinal peptide (VIP), are found in cell nucleus. As VIP receptors are involved in the regulation of glioma cell proliferation and migration, we investigated the expression and the nuclear localization of the VIP receptors VPAC1 and VPAC2 in this cancer. First, by applying Western blot and immunofluorescence detection in three human glioblastoma (GBM) cell lines, we observed a strong nuclear staining for the VPAC1 receptor and a weak nuclear VPAC2 receptor staining. Second, immunohistochemical staining of VPAC1 and VPAC2 on tissue microarrays (TMA) showed that the two receptors were expressed in normal brain and glioma tissues. Expression in the non-nuclear compartment of the two receptors significantly increased with the grade of the tumors. Analysis of nuclear staining revealed a significant increase of VPAC1 staining with glioma grade, with up to 50% of GBM displaying strong VPAC1 nuclear staining, whereas nuclear VPAC2 staining remained marginal. The increase in VPAC receptor expression with glioma grades and the enhanced nuclear localization of the VPAC1 receptors in GBM might be of importance for glioma progression.
    Full-text · Article · Oct 2014 · Biochemical and Biophysical Research Communications
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    • "G-protein-coupled receptors (GPCRs) are integral membrane proteins with seven α-helical hydrophobic domains that carry out specific physiological functions23. They are divided into several subfamilies based on sequence similarity24. "
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    ABSTRACT: G-protein-coupled receptors regulate signal transduction pathways and play diverse and pivotal roles in the physiology of insects, however, the precise function of GPCRs in insecticide resistance remains unclear. Using quantitative RT-PCR and functional genomic methods, we, for the first time, explored the function of GPCRs and GPCR-related genes in insecticide resistance of mosquitoes, Culex quinquefasciatus. A comparison of the expression of 115 GPCR-related genes at a whole genome level between resistant and susceptible Culex mosquitoes identified one and three GPCR-related genes that were up-regulated in highly resistant Culex mosquito strains, HAmCq(G8) and MAmCq(G6), respectively. To characterize the function of these up-regulated GPCR-related genes in resistance, the up-regulated GPCR-related genes were knockdown in HAmCq(G8) and MAmCq(G6) using RNAi technique. Knockdown of these four GPCR-related genes not only decreased resistance of the mosquitoes to permethrin but also repressed the expression of four insecticide resistance-related P450 genes, suggesting the role of GPCR-related genes in resistance is involved in the regulation of resistance P450 gene expression. This results help in understanding of molecular regulation of resistance development in Cx. quinquefasciatus.
    Full-text · Article · Sep 2014 · Scientific Reports
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