G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease

Kwon, Michelle; Pavlov, Tengis S.; Nozu, Kandai; Rasmussen, Shauna A.; Ilatovskaya, Daria V.; Lerch-Gaggl, Alexandra; North, Lauren M.; Kim, Hyunho; Qian, Feng; Sweeney, William E.; Avner, Ellis D.; Blumer, Joe B.; Staruschenko, Alexander; Park, Frank

doi:10.1073/pnas.1216830110

Cited by 36 publications

(94 citation statements)

References 64 publications

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“…It is interesting to speculate on the relative ratio of receptors coupling to Gabg versus GaGPR. Regulation of GPR protein expression levels may play a role in determining this stoichiometry, as AGS3 and AGS4 levels are responsive to changes in environmental and pathophysiological conditions, including withdrawal from drugs of abuse, ischemia/reperfusion injury, and leukocyte activation (Bowers et al, 2004(Bowers et al, , 2008Yao et al, 2005;Nadella et al, 2010;Regner et al, 2011;Kwon et al, 2012;Giguere et al, 2013;Branham-O'Connor et al, 2014;W. G. Robichaux, III and J.…”

Section: Resultsmentioning

confidence: 99%

Direct Coupling of a Seven-Transmembrane-Span Receptor to a Gαi G-Protein Regulatory Motif Complex

et al. 2015

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Group II activator of G-protein signaling (AGS) proteins contain one or more G-protein regulatory motifs (GPR), which serve as docking sites for Gai GDP independent of Gbg and stabilize the GDP-bound conformation of Gai, acting as guanine nucleotide dissociation inhibitors. The GaGPR interaction is regulated by seven-transmembrane-spanning (7TM) receptors in the intact cell as determined by bioluminescence resonance energy transfer (BRET). It is hypothesized that a 7TM receptor directly couples to the GaGPR complex in a manner analogous to receptor coupling to the Gabg heterotrimer. As an initial approach to test this hypothesis, we used BRET to examine 7TM receptor-mediated regulation of GaGPR in the intact cell when Gai 2 yellow fluorescent protein (YFP) was tethered to the carboxyl terminus of the a 2A adrenergic receptor (a 2A AR-Gai 2 YFP). AGS3-and AGS4-Renilla luciferase (Rluc) exhibited robust BRET with the tethered GaiYFP, and this interaction was regulated by receptor activation localizing the regulation to the receptor microenvironment. Agonist regulation of the receptor-Gai-GPR complex was also confirmed by coimmunoprecipitation and cell fractionation. The tethered Gai 2 was rendered pertussis toxin-insensitive by a C352I mutation, and receptor coupling to endogenous Gai/obg was subsequently eliminated by cell treatment with pertussis toxin (PT). Basal and agonist-induced regulation of a 2A ARGai 2 YFP C352I

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Section: Resultsmentioning

confidence: 99%

Direct Coupling of a Seven-Transmembrane-Span Receptor to a Gαi G-Protein Regulatory Motif Complex

et al. 2015

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“…Kidneys from sham and IRI operated rats were formalin fixed, paraffin embedded, and sectioned (4 mm) for immunostaining with PCNA as previously described by Kwon et al (2012). In brief, antigen retrieval was performed by heating (90°C) in antigen-retrieval solution (IHC World, Woodstock, MD); the slides were blocked then incubated with a primary antibody against proliferating cell nuclear antigen (PCNA; 1:1000 dilution).…”

Section: Methodsmentioning

confidence: 99%

“…More specifically, unilateral IRI in mice with a deficiency in full-length expression of GPSM1/AGS3 exhibited a decreased number of proliferating outer medullary proximal tubular cells and an increased number of persistently injured renal tubules compared with wild-type mice (Regner et al, 2011). Other accessory proteins have also been shown to regulate effectors through Gbg function (Takesono et al, 2002), including mitogen-activated protein kinase (MAPK) and phospholipase C signaling, ion channel activity, and mitotic spindle orientation (Sanada and Tsai, 2005;Lin and Smrcka, 2011;Kwon et al, 2012). Although there is a lack of pharmacologic inhibitors targeting AGS proteins, Gbg dimer function can be manipulated in vivo through the use of small molecule inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…However, GPSM1/AGS3 exerts its biologic effects by modulating the activity of unbound Gbg dimers (Sanada and Tsai, 2005;Bowers et al, 2008;Nadella et al, 2010;Kwon et al, 2012). We have previously shown that GPSM1/AGS3 modulates renal tubular repair through a Gbg-dependent mechanism in rodent models of renal ischemia-reperfusion injury (IRI) (Regner et al, 2011) and polycystic kidney disease (Nadella et al, 2010;Kwon et al, 2012). More specifically, unilateral IRI in mice with a deficiency in full-length expression of GPSM1/AGS3 exhibited a decreased number of proliferating outer medullary proximal tubular cells and an increased number of persistently injured renal tubules compared with wild-type mice (Regner et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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G-ProteinβγSubunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

White¹,

North²,

Haines³

et al. 2014

Mol Pharmacol

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Heterotrimeric G-proteins play a crucial role in the control of renal epithelial cell function during homeostasis and in response to injury. In this report, G-protein bg subunit (Gbg) dimer activity was evaluated during the process of tubular repair after renal ischemia-reperfusion injury (IRI) in male Sprague Dawley rats. Rats were treated with a small molecule inhibitor of Gbg activity, gallein (30 or 100 mg/kg), 1 hour after reperfusion and every 24 hours for 3 additional days. After IRI, renal dysfunction was prolonged after the high-dose gallein treatment in comparison with vehicle treatment during the 7-day recovery period. Renal tubular repair in the outer medulla 7 days after IRI was significantly (P , 0.001) attenuated after treatment with high-dose gallein (100 mg/kg) in comparison with low-dose gallein (30 mg/kg), or the vehicle and fluorescein control groups. Gallein treatment significantly reduced (P , 0.05) the number of proliferating cell nuclear antigen-positive tubular epithelial cells at 24 hours after the ischemia-reperfusion phase in vivo. In vitro application of gallein on normal rat kidney (NRK-52E) proximal tubule cells significantly reduced (P , 0.05) S-phase cell cycle entry compared with vehicletreated cells as determined by 59-bromo-29-deoxyuridine incorporation. Taken together, these data suggest that Gbg signaling contributes to the maintenance and repair of renal tubular epithelium and may be a novel therapeutic target for the development of drugs to treat acute kidney injury.

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“…In addition, G-protein-signaling modulator 1 (GPSM1) is able to upregulate the channel function of the polycystin complex via the G protein subunit. In the Pkd1 mouse model, complete deletion of GPSM1 promotes cyst formation and reduces renal function [80], indicating that GPSM1 may also play a role in GPCR activation of ADPKD.…”

Section: G Protein Signaling Pathwaymentioning

confidence: 99%

Present Status and Advances in Autosomal Dominant Polycystic Kidney Disease

Li¹

2017

Cell Mol Med

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder of the kidney. The mainly clinical manifestation is progressive cyst formation in bilateral kidneys, impairs normal renal parenchyma, and ultimately results in end-stage renal disease (ESRD). Extra-renal lesions include cystic liver or pancreas, brain aneurysm and cardiovascular defects. Mutations in either PKD1 or PKD2 genes result in the disease, but the former develops more severe clinical phenotypes than the latter. Currently, ADPKD still challenge vast clinicians on account of lacking effective and less side-effect therapy. Intensive study of molecular mechanism of the disease can establish theoretical basis for potential therapeutic targets and guide clinicians to develop new approaches in treatment of this disease. This review will focus on current advances of ADPKD pathogenesis which may benefit the translational therapy and precision medicine for the disease treatment. liver failure [25,26]. The prevalence of intracranial aneurysms (ICA) among ADPKD patients is about 12% [27]. A family history of intracranial hemorrhage can significantly increase the risk of ICA [28]. Therefore, examination and evaluation of extrarenal organ of ADPKD patients is also very important.At present, there is no safe and effective treatment of ADPKD in clinic. Therefore, understanding the pathogenesis of ADPKD may provide a new therapeutic target for the clinical treatment and lay the foundation for the development of various biological and drug treatments for ADPKD. [30,31]. Polycystin-1 is found in most segments of the nephron and is distributed in a variety of subcellular structures such as the primary cilia, cytoplasmic vesicles, plasma membrane at focal adhesions, desmosomes, adherens junctions, and possibly endoplasmic reticulum and nuclei. Among them, polycystin-1 distributed in primary cilia is considered to play an important role in the mechano/chemo-sensor function [32][33][34], whereas polycystin-1 distributed in the side wall and the basal body participates in the formation of intercellular adhesion and focal adhesion [35]. In addition, a cleavage product of polycystin-1 that includes the C-terminal tail can translocate to the nucleus and regulate gene transcription [36,37]. PKD Genes and Proteins

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G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease

Cited by 36 publications

References 64 publications

Direct Coupling of a Seven-Transmembrane-Span Receptor to a Gαi G-Protein Regulatory Motif Complex

Direct Coupling of a Seven-Transmembrane-Span Receptor to a Gαi G-Protein Regulatory Motif Complex

G-ProteinβγSubunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

Present Status and Advances in Autosomal Dominant Polycystic Kidney Disease

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