Journal articles: 'Gα15'

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Davignon, I., M. D. Catalina, D. Smith, J. Montgomery, J. Swantek, J. Croy, M. Siegelman, and T. M. Wilkie. "Normal Hematopoiesis and Inflammatory Responses Despite Discrete Signaling Defects in Gα15 Knockout Mice." Molecular and Cellular Biology 20, no. 3 (February 1, 2000): 797–804. http://dx.doi.org/10.1128/mcb.20.3.797-804.2000.

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ABSTRACT Gα15 activates phospholipase Cβ in response to the greatest variety of agonist-stimulated heptahelical receptors among the four Gq class G-protein α subunits expressed in mammals. Gα15 is primarily expressed in hematopoietic cells in fetal and adult mice. We disrupted the Gα15 gene by homologous recombination in embryonic stem cells to identify its biological functions. Surprisingly, hematopoiesis was normal in Gα15−/− mice, Gα15−/−Gαq−/− double-knockout mice (which express only Gα11 in most hematopoietic cells), and Gα11−/− mice, suggesting functional redundancy in Gq class signaling. Inflammatory challenges, including thioglycolate-induced peritonitis and infection with Trichinella spiralis, stimulated similar responses in Gα15−/− adults and wild-type siblings. Agonist-stimulated Ca2+ release from intracellular stores was assayed to identify signaling defects in primary cultures of thioglycolate-elicited macrophages isolated from Gα15−/− mice. C5a-stimulated phosphoinositide accumulation and Ca2+ release was significantly reduced in Gα15−/− macrophages. Ca2+ signaling was abolished only in mutant cells pretreated with pertussis toxin, suggesting that the C5a receptor couples to both Gα15 and Gαi in vivo. Signaling evoked by other receptors coupled by Gq class α subunits appeared normal in Gα15−/− macrophages. Despite discrete signaling defects, compensation by coexpressed Gq and/or Gi class α subunits may suppress abnormalities in Gα15-deficient mice.

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Yule, David I., Christopher W. Baker, and John A. Williams. "Calcium signaling in rat pancreatic acinar cells: a role for Gαq, Gα11, and Gα14." American Journal of Physiology-Gastrointestinal and Liver Physiology 276, no. 1 (January 1, 1999): G271—G279. http://dx.doi.org/10.1152/ajpgi.1999.276.1.g271.

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Stimulus-secretion coupling in the pancreatic acinar cell is initiated by the secretagogues CCK and ACh and results in the secretion by exocytosis of the contents of zymogen granules. A key event in this pathway is the G protein-activated production of second messengers and the subsequent elevation of cytosolic-free Ca2+. The aim of this study was therefore to define the heterotrimeric G protein α-subunits present and participating in this pathway in rat pancreatic acinar cells. RT-PCR products were amplified from pancreatic acinar cell mRNA with primers specific for Gαq, Gα11, and Gα14 but were not amplified with primers specific for Gα15. The sequences of these PCR products confirmed them to be portions of the rat homologues of Gαq, Gα11, and Gα14. The pancreatic-derived cell line AR42J similarly expressed Gαq, Gα11, and Gα14; however, the Chinese hamster ovary (CHO) cell line only expressed Gα11 and Gαq. These data indicate that caution should be exercised when comparing signal transduction pathways between different cell types. The expression of these proteins in acinar cells was confirmed by immunoblotting samples of acinar membrane protein using specific antisera to the individual G protein α-subunits. The role of these proteins in Ca2+ signaling events was investigated by microinjecting a neutralizing antibody directed against a homologous sequence in Gαq, Gα11, and Gα14 into acinar cells and CHO cells. Ca2+ signaling was inhibited in acinar cells and receptor-bearing CHO cells in response to both physiological and supermaximal concentrations of agonists. The inhibition was >75% in both cell types. These data indicate a role for Gαq and/or Gα11 in intracellular Ca2+ concentration signaling in CHO cells, and in addition to Gαq and Gα11, Gα14 may also fulfill this role in rat pancreatic acinar cells.

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van den Bos, Esther, Benjamin Ambrosy, Markus Horsthemke, Stefan Walbaum, Anne C. Bachg, Nina Wettschureck, Giulio Innamorati, Thomas M. Wilkie, and Peter J. Hanley. "Knockout mouse models reveal the contributions of G protein subunits to complement C5a receptor–mediated chemotaxis." Journal of Biological Chemistry 295, no. 22 (April 24, 2020): 7726–42. http://dx.doi.org/10.1074/jbc.ra119.011984.

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G protein–coupled receptor signaling is required for the navigation of immune cells along chemoattractant gradients. However, chemoattractant receptors may couple to more than one type of heterotrimeric G protein, each of which consists of a Gα, Gβ, and Gγ subunit, making it difficult to delineate the critical signaling pathways. Here, we used knockout mouse models and time-lapse microscopy to elucidate Gα and Gβ subunits contributing to complement C5a receptor-mediated chemotaxis. Complement C5a-mediated chemokinesis and chemotaxis were almost completely abolished in macrophages lacking Gnai2 (encoding Gαi2), consistent with a reduced leukocyte recruitment previously observed in Gnai2−/− mice, whereas cells lacking Gnai3 (Gαi3) exhibited only a slight decrease in cell velocity. Surprisingly, C5a-induced Ca2+ transients and lamellipodial membrane spreading were persistent in Gnai2−/− macrophages. Macrophages lacking both Gnaq (Gαq) and Gna11 (Gα11) or both Gna12 (Gα12) and Gna13 (Gα13) had essentially normal chemotaxis, Ca2+ signaling, and cell spreading, except Gna12/Gna13-deficient macrophages had increased cell velocity and elongated trailing ends. Moreover, Gnaq/Gna11-deficient cells did not respond to purinergic receptor P2Y2 stimulation. Genetic deletion of Gna15 (Gα15) virtually abolished C5a-induced Ca2+ transients, but chemotaxis and cell spreading were preserved. Homozygous Gnb1 (Gβ1) deletion was lethal, but mice lacking Gnb2 (Gβ2) were viable. Gnb2−/− macrophages exhibited robust Ca2+ transients and cell spreading, albeit decreased cell velocity and impaired chemotaxis. In summary, complement C5a-mediated chemotaxis requires Gαi2 and Gβ2, but not Ca2+ signaling, and membrane protrusive activity is promoted by G proteins that deplete phosphatidylinositol 4,5-bisphosphate.

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Feild, John A., James J. Foley, Tania T. Testa, Parvathi Nuthulaganti, Catherine Ellis, Henry M. Sarau, and Robert S. Ames. "Cloning and characterization of a rabbit ortholog of human Gα16 and mouse Gα15." FEBS Letters 460, no. 1 (October 22, 1999): 53–56. http://dx.doi.org/10.1016/s0014-5793(99)01317-4.

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GAUDREAU, Rémi, Christian Le GOUILL, Salim MÉTAOUI, Stéphane LEMIRE, Jana STANKOVÀ, and Marek ROLA-PLESZCZYNSKI. "Signalling through the leukotriene B4 receptor involves both αi and α16, but not αq or α11 G-protein subunits." Biochemical Journal 335, no. 1 (October 1, 1998): 15–18. http://dx.doi.org/10.1042/bj3350015.

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COS-7 cells transfected with the leukotriene (LT) B4 receptor (BLTR) cDNA were unable to produce LTB4-induced inositol phosphates (IPs) in spite of the presence of endogenous Gαi, Gαq and Gα11 proteins. Co-transfection of BLTR with Gα16, however, resulted in high levels of IP production, which were 17-, 10- and 6-fold higher than with co-transfected Gα11, Gαq and Gα14, respectively. Co-transfection of BLTR with phospholipase C (PLC) β2, on the other hand, resulted in efficient IP production and co-transfection of BLTR with both Gα16 and PLCβ2 resulted in a greater than additive response.

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Rafa-Zabłocka, Katarzyna, Agnieszka Zelek-Molik, Beata Tepper, Piotr Chmielarz, Grzegorz Kreiner, Michał Wilczkowski, and Irena Nalepa. "Chronic restraint stress induces changes in the cerebral Galpha 12/13 and Rho-GTPase signaling network." Pharmacological Reports 73, no. 4 (June 11, 2021): 1179–87. http://dx.doi.org/10.1007/s43440-021-00294-4.

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Abstract Background Evidence indicates that Gα12, Gα13, and its downstream effectors, RhoA and Rac1, regulate neuronal morphology affected by stress. This study was aimed at investigating whether repeated stress influences the expression of proteins related to the Gα12/13 intracellular signaling pathway in selected brain regions sensitive to the effects of stress. Furthermore, the therapeutic impact of β(1)adrenergic receptors (β1AR) blockade was assessed. Methods Restraint stress (RS) model in mice (2 h/14 days) was used to assess prolonged stress effects on the mRNA expression of Gα12, Gα13, RhoA, Rac1 in the prefrontal cortex (PFC), hippocampus (HIP) and amygdala (AMY). In a separate study, applying RS model in rats (3–4 h/1 day or 14 days), we evaluated stress effects on the expression of Gα12, Gα11, Gαq, RhoA, RhoB, RhoC, Rac1/2/3 in the HIP. Betaxolol (BET), a selective β1AR antagonist, was introduced (5 mg/kg/p.o./8–14 days) in the rat RS model to assess the role of β1AR in stress effects. RT-qPCR and Western Blot were used for mRNA and protein assessments, respectively. Results Chronic RS decreased mRNA expression of Gα12 and increased mRNA for Rac1 in the PFC of mice. In the mice AMY, decreased mRNA expression of Gα12, Gα13 and RhoA was observed. Fourteen days of RS exposure increased RhoA protein level in the rats’ HIP in the manner dependent on β1AR activity. Conclusions Together, these results suggest that repeated RS affects the expression of genes and proteins known to be engaged in neural plasticity, providing potential targets for further studies aimed at unraveling the molecular mechanisms of stress-related neuropsychiatric diseases.

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Cho, Min Kyung, Won Dong Kim, Sung Hwan Ki, Jong-Ik Hwang, Sangdun Choi, Chang Ho Lee, and Sang Geon Kim. "Role of Gα12 and Gα13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor." Molecular and Cellular Biology 27, no. 17 (June 25, 2007): 6195–208. http://dx.doi.org/10.1128/mcb.02065-06.

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ABSTRACT Gα12 and Gα13 function as molecular regulators responding to extracellular stimuli. NF-E2-related factor 2 (Nrf2) is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by Gα12 and Gα13. A deficiency of Gα12, but not of Gα13, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, Gα12 knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin and its glucuronosyl conjugations. An oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by Gα12 gene knockout. Gα12 deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did Gα13 deficiency. The absence of Gα12, but not of Gα13, increased protein kinase C δ (PKC δ) activation and the PKC δ-mediated serine phosphorylation of Nrf2. Gα13 gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by Gα12 deficiency, suggesting that relief from Gα12 repression leads to the Gα13-mediated activation of Nrf2. Constitutive activation of Gα13 promoted Nrf2 activity and target gene induction via Rho-mediated PKC δ activation, corroborating positive regulation by Gα13. In summary, Gα12 and Gα13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas Gα13 regulates Rho-PKC δ-mediated Nrf2 phosphorylation, which is negatively balanced by Gα12.

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McNeil Coffield, V., Whitney S. Helms, Qi Jiang, and Lishan Su. "Gα13 Mediates a Signal That Is Essential for Proliferation and Survival of Thymocyte Progenitors." Journal of Experimental Medicine 200, no. 10 (November 8, 2004): 1315–24. http://dx.doi.org/10.1084/jem.20040944.

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G protein signaling via the Gα12 family (Gα12 and Gα13) has not been well studied in T cells. To investigate whether Gα12 and Gα13 are involved in thymopoiesis, we expressed the regulator of G protein signaling domain of p115RhoGEF to inhibit Gα12 and Gα13 during thymopoiesis. Fetal thymus organ cultures seeded with p115ΔDH-expressing progenitor cells showed impaired thymopoiesis with a block at the CD4−CD8−CD44−CD25+ (DN3) stage. Using Gα13 or Gα12 minigenes, we demonstrated that Gα13, but not Gα12, is required for thymopoiesis. T progenitor cells expressing p115ΔDH showed reduced proliferation and increased cell death. T cell receptor stimulation of the fetal thymus organ cultures did not rescue the block. Overexpression of the antiapoptotic gene Bcl2 rescued the defect in DN3 cells and partially rescued T cell development. Therefore, Gα13-mediated signaling is necessary in early thymocyte proliferation and survival.

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Tutunea-Fatan, Elena, Jasper C. Lee, Bradley M. Denker, and Lakshman Gunaratnam. "Heterotrimeric Gα12/13 proteins in kidney injury and disease." American Journal of Physiology-Renal Physiology 318, no. 3 (March 1, 2020): F660—F672. http://dx.doi.org/10.1152/ajprenal.00453.2019.

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Gα12 and Gα13 are ubiquitous members of the heterotrimeric guanine nucleotide-binding protein (G protein) family that play central and integrative roles in the regulation of signal transduction cascades within various cell types in the kidney. Gα12/Gα13 proteins enable the kidney to adapt to an ever-changing environment by transducing stimuli from cell surface receptors and accessory proteins to effector systems. Therefore, perturbations in Gα12/Gα13 levels or their activity can contribute to the pathogenesis of various renal diseases, including renal cancer. This review will highlight and discuss the complex and expanding roles of Gα12/Gα13 proteins on distinct renal pathologies, with emphasis on more recently reported findings. Deciphering how the different Gα12/Gα13 interaction networks participate in the onset and development of renal diseases may lead to the discovery of new therapeutic strategies.

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Luo, W., L. R. Latchney, and D. J. Culp. "G protein coupling to M1 and M3muscarinic receptors in sublingual glands." American Journal of Physiology-Cell Physiology 280, no. 4 (April 1, 2001): C884—C896. http://dx.doi.org/10.1152/ajpcell.2001.280.4.c884.

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Rat sublingual gland M1 and M3 muscarinic receptors each directly activate exocrine secretion. To investigate the functional role of coreceptor expression, we determined receptor-G protein coupling. Although membrane proteins of 40 and 41 kDa are ADP-ribosylated by pertussis toxin (PTX), and 44 kDa proteins by cholera toxin (CTX), both carbachol-stimulated high-affinity GTPase activity and the GTP-induced shift in agonist binding are insensitive to CTX or PTX. Carbachol enhances photoaffinity labeling ([α-32P]GTP-azidoaniline) of only 42-kDa proteins that are subsequently tractable to immunoprecipitation by antibodies specific for Gαq or Gα11 but not Gα12 or Gα13. Carbachol-stimulated photoaffinity labeling as well as phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis is reduced 55% and 60%, respectively, by M1 receptor blockade with m1-toxin. Gαq/11-specific antibody blocks carbachol-stimulated PIP2 hydrolysis. We also provide estimates of the molar ratios of receptors to Gαq and Gα11. Although simultaneous activation of M1 and M3receptors is required for a maximal response, both receptor subtypes are coupled to Gαq and Gα11 to stimulate exocrine secretion via redundant mechanisms.

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Dettlaff-Swiercz, Dagmara A., Nina Wettschureck, Alexandra Moers, Katrin Huber, and Stefan Offermanns. "Characteristic defects in neural crest cell-specific Gαq/Gα11- and Gα12/Gα13-deficient mice." Developmental Biology 282, no. 1 (June 2005): 174–82. http://dx.doi.org/10.1016/j.ydbio.2005.03.006.

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Lin, Fang, Diane S. Sepich, Songhai Chen, Jacek Topczewski, Chunyue Yin, Lilianna Solnica-Krezel, and Heidi Hamm. "Essential roles of Gα12/13 signaling in distinct cell behaviors driving zebrafish convergence and extension gastrulation movements." Journal of Cell Biology 169, no. 5 (May 31, 2005): 777–87. http://dx.doi.org/10.1083/jcb.200501104.

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Gα12/13 have been implicated in numerous cellular processes, however, their roles in vertebrate gastrulation are largely unknown. Here, we show that during zebrafish gastrulation, suppression of both Gα12 and Gα13 signaling by overexpressing dominant negative proteins and application of antisense morpholino-modified oligonucleotide translation interference disrupted convergence and extension without changing embryonic patterning. Analyses of mesodermal cell behaviors revealed that Gα12/13 are required for cell elongation and efficient dorsalward migration during convergence independent of noncanonical Wnt signaling. Furthermore, Gα12/13 function cell-autonomously to mediate mediolateral cell elongation underlying intercalation during notochord extension, likely acting in parallel to noncanonical Wnt signaling. These findings provide the first evidence that Gα12 and Gα13 have overlapping and essential roles in distinct cell behaviors that drive vertebrate gastrulation.

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Abid, Hasnat Ali, Asuka Inoue, and Caroline M. Gorvin. "Heterogeneity of G protein activation by the calcium-sensing receptor." Journal of Molecular Endocrinology 67, no. 2 (August 1, 2021): 41–53. http://dx.doi.org/10.1530/jme-21-0058.

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The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that plays a fundamental role in extracellular calcium (Ca2+e) homeostasis by regulating parathyroid hormone release and urinary calcium excretion. The CaSR has been described to activate all four G protein subfamilies (Gαq/11, Gαi/o, Gα12/13, Gαs), and mutations in the receptor that cause hyper/hypocalcaemia, have been described to bias receptor signalling. However, many of these studies are based on measurements of second messengers or gene transcription that occurs many steps downstream of receptor activation and can represent convergence points of several signalling pathways. Therefore, to assess CaSR-mediated G protein activation directly, we took advantage of a recently described NanoBiT G protein dissociation assay system. Our studies, performed in HEK293 cells stably expressing CaSR, demonstrate that Ca2+e stimulation activates all Gαq/11 family and several Gαi/o family proteins, although Gαz was not activated. CaSR stimulated dissociation of Gα12/13 and Gαs from Gβ-subunits, but this occurred at a slower rate than that of other Gα-subunits. Investigation of cDNA expression of G proteins in three tissues abundantly expressing CaSR, the parathyroids, kidneys and pancreas, showed Gα11, Gαz, Gαi1 and Gα13 genes were highly expressed in parathyroid tissue, indicating CaSR most likely activates Gα11 and Gαi1 in parathyroids. In kidney and pancreas, the majority of G proteins were similarly expressed, suggesting CaSR may activate multiple G proteins in these cells. Thus, these studies validate a single assay system that can be used to robustly assess CaSR variants and biased signalling and could be utilised in the development of new pharmacological compounds targeting CaSR.

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Korhonen, Hanna, Beate Fisslthaler, Alexandra Moers, Angela Wirth, Daniel Habermehl, Thomas Wieland, Günther Schütz, Nina Wettschureck, Ingrid Fleming, and Stefan Offermanns. "Anaphylactic shock depends on endothelial Gq/G11." Journal of Experimental Medicine 206, no. 2 (January 26, 2009): 411–20. http://dx.doi.org/10.1084/jem.20082150.

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Anaphylactic shock is a severe allergic reaction involving multiple organs including the bronchial and cardiovascular system. Most anaphylactic mediators, like platelet-activating factor (PAF), histamine, and others, act through G protein–coupled receptors, which are linked to the heterotrimeric G proteins Gq/G11, G12/G13, and Gi. The role of downstream signaling pathways activated by anaphylactic mediators in defined organs during anaphylactic reactions is largely unknown. Using genetic mouse models that allow for the conditional abrogation of Gq/G11- and G12/G13-mediated signaling pathways by inducible Cre/loxP-mediated mutagenesis in endothelial cells (ECs), we show that Gq/G11-mediated signaling in ECs is required for the opening of the endothelial barrier and the stimulation of nitric oxide formation by various inflammatory mediators as well as by local anaphylaxis. The systemic effects of anaphylactic mediators like histamine and PAF, but not of bacterial lipopolysaccharide (LPS), are blunted in mice with endothelial Gαq/Gα11 deficiency. Mice with endothelium-specific Gαq/Gα11 deficiency, but not with Gα12/Gα13 deficiency, are protected against the fatal consequences of passive and active systemic anaphylaxis. This identifies endothelial Gq/G11-mediated signaling as a critical mediator of fatal systemic anaphylaxis and, hence, as a potential new target to prevent or treat anaphylactic reactions.

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Booden, Michelle A., David P. Siderovski, and Channing J. Der. "Leukemia-Associated Rho Guanine Nucleotide Exchange Factor Promotes Gαq-Coupled Activation of RhoA." Molecular and Cellular Biology 22, no. 12 (June 15, 2002): 4053–61. http://dx.doi.org/10.1128/mcb.22.12.4053-4061.2002.

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ABSTRACT Leukemia-associated Rho guanine-nucleotide exchange factor (LARG) belongs to the subfamily of Dbl homology RhoGEF proteins (including p115 RhoGEF and PDZ-RhoGEF) that possess amino-terminal regulator of G protein signaling (RGS) boxes also found within GTPase-accelerating proteins (GAPs) for heterotrimeric G protein α subunits. p115 RhoGEF stimulates the intrinsic GTP hydrolysis activity of Gα12/13 subunits and acts as an effector for G13-coupled receptors by linking receptor activation to RhoA activation. The presence of RGS box and Dbl homology domains within LARG suggests this protein may also function as a GAP toward specific Gα subunits and couple Gα activation to RhoA-mediating signaling pathways. Unlike the RGS box of p115 RhoGEF, the RGS box of LARG interacts not only with Gα12 and Gα13 but also with Gαq. In cellular coimmunoprecipitation studies, the LARG RGS box formed stable complexes with the transition state mimetic forms of Gαq, Gα12, and Gα13. Expression of the LARG RGS box diminished the transforming activity of oncogenic G protein-coupled receptors (Mas, G2A, and m1-muscarinic cholinergic) coupled to Gαq and Gα13. Activated Gαq, as well as Gα12 and Gα13, cooperated with LARG and caused synergistic activation of RhoA, suggesting that all three Gα subunits stimulate LARG-mediated activation of RhoA. Our findings suggest that the RhoA exchange factor LARG, unlike the related p115 RhoGEF and PDZ-RhoGEF proteins, can serve as an effector for Gq-coupled receptors, mediating their functional linkage to RhoA-dependent signaling pathways.

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Singh, A. T. K., A. Gilchrist, T. Voyno-Yasenetskaya, J. M. Radeff-Huang, and P. H. Stern. "Gα12/Gα13 Subunits of Heterotrimeric G Proteins Mediate Parathyroid Hormone Activation of Phospholipase D in UMR-106 Osteoblastic Cells." Endocrinology 146, no. 5 (May 1, 2005): 2171–75. http://dx.doi.org/10.1210/en.2004-1283.

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Abstract PTH, a major regulator of bone remodeling and a therapeutically effective bone anabolic agent, stimulates several signaling pathways in osteoblastic cells. Our recent studies have revealed that PTH activates phospholipase D (PLD) -mediated phospholipid hydrolysis through a RhoA-dependent mechanism in osteoblastic cells, raising the question of the upstream link to the PTH receptor. In the current study, we investigated the role of heterotrimeric G proteins in mediating PTH-stimulated PLD activity in UMR-106 osteoblastic cells. Transfection with antagonist minigenes coding for small peptide antagonists to Gα12 and Gα13 subunits of heterotrimeric G proteins prevented PTH-stimulated activation of PLD, whereas an antagonist minigene to Gαs failed to produce this effect. Effects of pharmacological inhibitors (protein kinase inhibitor, Clostridium botulinum exoenzyme C3) were consistent with a role of Rho small G proteins, but not of cAMP, in the effect of PTH on PLD. Expression of constitutively active Gα12 and Gα13 activated PLD, an effect that was inhibited by dominant-negative RhoA. The results identify Gα12 and Gα13 as upstream transducers of PTH effects on PLD, mediated through RhoA in osteoblastic cells.

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Pauwels, P. J., S. Tardif, F. Finana, T. Wurch, and F. C. Colpaert. "Ligand-Receptor Interactions as Controlled by Wild-Type and Mutant Thr370Lys α2B-Adrenoceptor-Gα15 Fusion Proteins." Journal of Neurochemistry 74, no. 1 (December 25, 2001): 375–84. http://dx.doi.org/10.1046/j.1471-4159.2000.0740375.x.

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HARHAMMER, Rainer, Bernd NÜRNBERG, Christian HARTENECK, Daniela LEOPOLDT, Torsten EXNER, and Günter SCHULTZ. "Distinct biochemical properties of the native members of the G12 G-protein subfamily. Characterization of Gα12 purified from rat brain." Biochemical Journal 319, no. 1 (October 1, 1996): 165–71. http://dx.doi.org/10.1042/bj3190165.

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G12 and G13 are insufficiently characterized pertussis toxin-insensitive G-proteins. Here, we describe the isolation of Gα12 from rat brain membranes. Gα12 was purified to apparent homogeneity by three steps of conventional chromatography, followed by two cycles of subunit-exchange chromatography on immobilized G subunits. Purified Gα12 bound guanosine 5´-[γ-thio]triphosphate slowly and substoichiometrically. For isolation of functionally active Gα12, it was mandatory to use sucrose monolaurate as a detergent. Comparative studies of both rat-brain-derived members of the G12 subfamily revealed differences in the affinity of Gα12 and Gα13 for Gβγ. Gα12 required a higher Mg2+ concentration for AlF4--induced dissociation from immobilized Gβγ than did Gα13. In addition, the G12 subfamily members differed in their sedimentation velocities, as determined by sucrose-density-gradient centrifugation. Analysis of sedimentation coefficients revealed a higher tendency of G12 to form supramolecular structures in comparison to G13 and other G-proteins. These G12 structures were stabilized by sucrose monolaurate, which in turn may explain the necessity for this detergent for purification of functionally active Gα12. Despite these distinct biochemical characteristics of G12 and G13, both purified G-proteins coupled to a recombinant thromboxane A2 (TXA2) receptor reconstituted into phospholipid vesicles. These data indicate, (1) significant differences in the biochemical properties of native members of the G12 subfamily, and (2) their specific coupling to TXA2 receptors.

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Wang, Dawei, Ying-cai Tan, Geri E. Kreitzer, Yoko Nakai, Dandan Shan, Yi Zheng, and Xin-Yun Huang. "G Proteins G12 and G13 Control the Dynamic Turnover of Growth Factor-induced Dorsal Ruffles." Journal of Biological Chemistry 281, no. 43 (August 30, 2006): 32660–67. http://dx.doi.org/10.1074/jbc.m604588200.

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Growth factors induce massive actin cytoskeletal remodeling in cells. These reorganization events underlie various cellular responses such as cell migration and morphological changes. One major form of actin reorganization is the formation and disassembly of dorsal ruffles (also named waves, dorsal rings, or circular ruffles). Dorsal ruffles are involved in physiological functions including cell migration, invasion, macropinocytosis, plasma membrane recycling, and others. Growth factors initiate rapid formation (within 5 min) of circular membrane ruffles, and these ruffles move along the dorsal side of the cells, constrict, close, and eventually disassemble (∼20 min). Considerable attention has been devoted to the mechanism by which growth factors induce the formation of dorsal ruffles. However, little is known of the mechanism by which these ruffles are disassembled. Here we have shown that G proteins G12 and G13 control the rate of disassembly of dorsal ruffles. In Gα12-/-Gα13-/- fibroblast cells, dorsal ruffles induced by growth factor treatment remain visible substantially longer (∼60 min) than in wild-type cells, whereas the rate of formation of these ruffles was the same with or without Gα12 and Gα13. Thus, Gα12/Gα13 critically regulate dorsal ruffle turnover.

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Rasheed, Suhail Ahmed Kabeer, Lalitha Vaishnavi Subramanyan, Wei Kiang Lim, Udhaya Kumari Udayappan, Mei Wang, and Patrick J. Casey. "The emerging roles of Gα12/13 proteins on the hallmarks of cancer in solid tumors." Oncogene 41, no. 2 (October 23, 2021): 147–58. http://dx.doi.org/10.1038/s41388-021-02069-w.

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AbstractG12 proteins comprise a subfamily of G-alpha subunits of heterotrimeric GTP-binding proteins (G proteins) that link specific cell surface G protein-coupled receptors (GPCRs) to downstream signaling molecules and play important roles in human physiology. The G12 subfamily contains two family members: Gα12 and Gα13 (encoded by the GNA12 and GNA13 genes, respectively) and, as with all G proteins, their activity is regulated by their ability to bind to guanine nucleotides. Increased expression of both Gα12 and Gα13, and their enhanced signaling, has been associated with tumorigenesis and tumor progression of multiple cancer types over the past decade. Despite these strong associations, Gα12/13 proteins are underappreciated in the field of cancer. As our understanding of G protein involvement in oncogenic signaling has evolved, it has become clear that Gα12/13 signaling is pleotropic and activates specific downstream effectors in different tumor types. Further, the expression of Gα12/13 proteins is regulated through a series of transcriptional and post-transcriptional mechanisms, several of which are frequently deregulated in cancer. With the ever-increasing understanding of tumorigenic processes driven by Gα12/13 proteins, it is becoming clear that targeting Gα12/13 signaling in a context-specific manner could provide a new strategy to improve therapeutic outcomes in a number of solid tumors. In this review, we detail how Gα12/13 proteins, which were first discovered as proto-oncogenes, are now known to drive several “classical” hallmarks, and also play important roles in the “emerging” hallmarks, of cancer.

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Sabbatini, Maria E., Yan Bi, Baoan Ji, Stephen A. Ernst, and John A. Williams. "CCK activates RhoA and Rac1 differentially through Gα13 and Gαq in mouse pancreatic acini." American Journal of Physiology-Cell Physiology 298, no. 3 (March 2010): C592—C601. http://dx.doi.org/10.1152/ajpcell.00448.2009.

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Cholecystokinin (CCK) has been shown to activate RhoA and Rac1, as well as reorganize the actin cytoskeleton and, thereby, modify acinar morphology and amylase secretion in mouse pancreatic acini. The aim of the present study was to determine which heterotrimeric G proteins activate RhoA and Rac1 upon CCK stimulation. Gα13, but not Gα12, was identified in mouse pancreatic acini by RT-PCR and Western blotting. Using specific assays for RhoA and Rac1 activation, we showed that only active Gα13 activated RhoA. By contrast, active Gα13 and Gαq, but not Gαs, slightly increased GTP-bound Rac1 levels. A greater increase in Rac1 activation was observed when active Gα13 and active Gαq were coexpressed. Gαi was not required for CCK-induced RhoA or Rac1 activation. The regulator of G protein signaling (RGS) domain of p115-Rho guanine nucleotide exchange factor (p115-RGS), a specific inhibitor of Gα12/13-mediated signaling, abolished CCK-stimulated RhoA activation. By contrast, both RGS-2, an inhibitor of Gαq, and p115-RGS abolished CCK-induced Rac1 activation, which was PLC pathway-independent. Active Gαq and Gα13, but not Gαs, induced morphological changes and actin redistribution similar to 1 nM CCK. CCK-induced actin cytoskeletal reorganization was inhibited by RGS-2, but not by p115-RGS, whereas CCK-induced amylase secretion was blocked by both inhibitors. Together, these findings indicate that, in mouse pancreatic acini, Gα13 links CCK stimulation to the activation of RhoA, whereas both Gα13 and Gαq link CCK stimulation to the activation of Rac1. CCK-induced actin cytoskeletal reorganization is mainly mediated by Gαq. By contrast, Gα13 and Gαq signaling are required for CCK-induced amylase secretion.

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Kusakabe, Yuko, Eiri Yamaguchi, Kentaro Tanemura, Kimihiko Kameyama, Noboru Chiba, Soichi Arai, Yasufumi Emori, and Keiko Abe. "Identification of two α-subunit species of GTP-binding proteins, Gα15 and Gαq, expressed in rat taste buds." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1403, no. 3 (July 1998): 265–72. http://dx.doi.org/10.1016/s0167-4889(98)00062-7.

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Althoff, Till F., Julián Albarrán Juárez, Kerstin Troidl, Cong Tang, Shengpeng Wang, Angela Wirth, Mikito Takefuji, Nina Wettschureck, and Stefan Offermanns. "Procontractile G protein–mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling." Journal of Experimental Medicine 209, no. 12 (November 5, 2012): 2277–90. http://dx.doi.org/10.1084/jem.20120350.

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Vascular smooth muscle (Sm) cells (VSMCs) are highly plastic. Their differentiation state can be regulated by serum response factor (SRF), which activates genes involved in Sm differentiation and proliferation by recruiting cofactors, such as members of the myocardin family and ternary complex factors (TCFs), respectively. However, the extracellular cues and upstream signaling mechanisms regulating SRF-dependent VSMC differentiation under in vivo conditions are poorly understood. In this study, we show that the procontractile signaling pathways mediated by the G proteins G12/G13 and Gq/G11 antagonistically regulate VSMC plasticity in different models of vascular remodeling. In mice lacking Gα12/Gα13 or their effector, the RhoGEF protein LARG, RhoA-dependent SRF-regulation was blocked and down-regulation of VSMC differentiation marker genes was enhanced. This was accompanied by an excessive vascular remodeling and exacerbation of atherosclerosis. In contrast, Sm-specific Gαq/Gα11 deficiency blocked activation of extracellular signal-regulated kinase 1/2 and the TCF Elk-1, resulting in a reduced VSMC dedifferentiation in response to flow cessation or vascular injury. These data show that the balanced activity of both G protein–mediated pathways in VSMCs is required for an appropriate vessel remodeling response in vascular diseases and suggest new approaches to modulate Sm differentiation in vascular pathologies.

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ZHU, Ting, Li-yan FANG, and Xin XIE. "Development of a universal high-throughput calcium assay for G-protein-coupled receptors with promiscuous G-protein Gα15/16." Acta Pharmacologica Sinica 29, no. 4 (April 2008): 507–16. http://dx.doi.org/10.1111/j.1745-7254.2008.00775.x.

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Lucey, M., and K. L. van Golen. "THE HETEROTRIMERIC G-PROTEIN, Gα15/16, PROMOTES CELLULAR INVASION VIA THE SMALL GTP-BINDING PROTEIN, RAS HOMOLOGOUS C (RHOC)." Pancreas 37, no. 4 (November 2008): 482. http://dx.doi.org/10.1097/01.mpa.0000335509.52441.12.

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Goulimari, Polyxeni, Helga Knieling, Ulrike Engel, and Robert Grosse. "LARG and mDia1 Link Gα12/13 to Cell Polarity and Microtubule Dynamics." Molecular Biology of the Cell 19, no. 1 (January 2008): 30–40. http://dx.doi.org/10.1091/mbc.e06-11-1045.

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Regulation of cell polarity is a process observed in all cells. During directed migration, cells orientate their microtubule cytoskeleton and the microtubule-organizing-center (MTOC), which involves integrins and downstream Cdc42 and glycogen synthase kinase-3β activity. However, the contribution of G protein-coupled receptor signal transduction for MTOC polarity is less well understood. Here, we report that the heterotrimeric Gα12 and Gα13 proteins are necessary for MTOC polarity and microtubule dynamics based on studies using Gα12/13-deficient mouse embryonic fibroblasts. Cell polarization involves the Gα12/13-interacting leukemia-associated RhoGEF (LARG) and the actin-nucleating diaphanous formin mDia1. Interestingly, LARG associates with pericentrin and localizes to the MTOC and along microtubule tracks. We propose that Gα12/13 proteins exert essential functions linking extracellular signals to microtubule dynamics and cell polarity via RhoGEF and formin activity.

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Melnychuk, Ryan M., Daniel N. Streblow, Patricia P. Smith, Alec J. Hirsch, Dora Pancheva, and Jay A. Nelson. "Human Cytomegalovirus-Encoded G Protein-Coupled Receptor US28 Mediates Smooth Muscle Cell Migration through Gα12." Journal of Virology 78, no. 15 (August 1, 2004): 8382–91. http://dx.doi.org/10.1128/jvi.78.15.8382-8391.2004.

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ABSTRACT Coupling of G proteins to ligand-engaged chemokine receptors is the paramount event in G-protein-coupled receptor signal transduction. Previously, we have demonstrated that the human cytomegalovirus-encoded chemokine receptor US28 mediates human vascular smooth muscle cell (SMC) migration in response to either RANTES or monocyte chemoattractant protein 1. In this report, we identify the G proteins that couple with US28 to promote vascular SMC migration and identify other signaling molecules that play critical roles in this process. US28-mediated cellular migration was enhanced with the expression of the G-protein subunits Gα12 and Gα13, suggesting that US28 may functionally couple to these G proteins. In correlation with this observation, US28 was able to activate RhoA, a downstream effector of Gα12 and Gα13 in cell types with these G proteins but not in those without them and activation of RhoA was dependent on US28 stimulation with RANTES. In addition, inactivation of RhoA or the RhoA-associated kinase p160ROCK with a dominant-negative mutant of RhoA or the small molecule inhibitor Y27632, respectively, abrogated US28-induced SMC migration. The data presented here suggest that US28 functionally signals through Gα12 family G proteins and RhoA in a ligand-dependent manner and these signaling molecules are important for the ability of US28 to induce cellular migration.

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Temirak, Ahmed, Jonathan G. Schlegel, Jan H. Voss, Victoria J. Vaaßen, Christin Vielmuth, Tobias Claff, and Christa E. Müller. "Irreversible Antagonists for the Adenosine A2B Receptor." Molecules 27, no. 12 (June 13, 2022): 3792. http://dx.doi.org/10.3390/molecules27123792.

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Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand binding and bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out and kinetic experiments. p-(1-Propylxanthin-8-yl)benzene sulfonyl fluoride (6a, PSB-21500) was the most potent and selective irreversible A2BAR antagonist of the present series with an apparent Ki value of 10.6 nM at the human A2BAR and >38-fold selectivity versus the other AR subtypes. The corresponding 3-cyclopropyl-substituted xanthine derivative 6c (PSB-21502) was similarly potent, but was non-selective versus A1- and A2AARs. Attachment of a reactive sulfonyl fluoride group to an elongated xanthine 8-substituent (12, Ki 7.37 nM) resulted in a potent, selective, reversibly binding antagonist. Based on previous docking studies, the lysine residue K2697.32 was proposed to react with the covalent antagonists. However, the mutant K269L behaved similarly to the wildtype A2BAR, indicating that 6a and related irreversible A2BAR antagonists do not interact with K2697.32. The new irreversible A2BAR antagonists will be useful tools and have the potential to be further developed as therapeutic drugs.

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DAVIS, Mark G., Yumiko KAWAI, and Ifeanyi J. ARINZE. "Involvement of Giα2 in sodium butyrate-induced erythroblastic differentiation of K562 cells." Biochemical Journal 346, no. 2 (February 22, 2000): 455–61. http://dx.doi.org/10.1042/bj3460455.

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The chronic myelogenous leukaemia cell line K562 can be triggered in culture to differentiate along the erythrocytic pathway in response to a variety of stimulatory agents. In the presence of sodium butyrate, these cells differentiate to erythroblasts and acquire the capability to synthesize haemoglobin. We used this cell system to study alterations in the levels of several G-protein subunits during the cell differentiation programme and to assess the involvement of Giα2 in this process. Western immunoblot analysis revealed the presence of Gsα1, Gsα2, Giα2, Gqα, Gα12, Gβ1 and Gβ2 in K562 cells. Goα, Gzα, Gα13 and Gα16 were not detected. Although the levels of several G-protein subunits were altered after treatment with sodium butyrate, the most striking change was the robust increase in the levels of Giα2, which was accompanied by an increase in the mRNA for Giα2. Inactivation of Giα2 by adding Bordetella pertussis toxin to the cultures inhibited erythroblastic differentiation by as much as 62%, as measured by haemoglobin accumulation. Furthermore, the addition of an oligonucleotide anti-sense to Giα2 inhibited the sodium butyrate-induced robust increase in Giα2 levels, decreasing it to the basal levels seen in control cells; this treatment decreased the erythroblastic differentiation of the cells (as measured by haemoglobin expression) by 50%. Taken together, these findings imply that increased levels of Giα2 contribute to the sodium butyrate-induced erythroblastic differentiation of K562 cells.

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Guilini, Célia, Kyoji Urayama, Gulen Turkeri, Deniz B. Dedeoglu, Hitoshi Kurose, Nadia Messaddeq, and Canan G. Nebigil. "Divergent roles of prokineticin receptors in the endothelial cells: angiogenesis and fenestration." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 3 (March 2010): H844—H852. http://dx.doi.org/10.1152/ajpheart.00898.2009.

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Prokineticins are secreted peptides that activate two G protein-coupled receptors: PKR1 and PKR2. Prokineticins induce angiogenesis and fenestration, but the cognate receptors involved in these functions are unknown. We hypothesized a role for prokineticin receptor signaling pathways and expression profiles in determining the selective effects of prokineticins on coronary endothelial cells (H5V). Activation of the PKR1/MAPK/Akt signaling pathway stimulates proliferation, migration, and angiogenesis in H5V cells, in which PKR1 predominates over PKR2. PKR1 was colocalized with Gα11 and was internalized following the stimulation of these cells with prokineticin-2. Knock down of PKR1 or Gα11 expression in H5V cells effectively inhibited prokineticin-2-induced vessel formation and MAPK/Akt activation, indicating a role for PKR1/Gα11 in this process. However, in conditions in which PKR2 predominated over PKR1, these cells displayed a fenestrated endothelial cell phenotype. H5V cells overexpressing PKR2 displayed large numbers of multivesicular bodies and caveolar clusters and a disruption of the distribution of zonula occluden-1 tight junction protein. Prokineticin-2 induced the colocalization of PKR2 with Gα12, and activated Gα12, which bound to zonula occluden-1 to trigger the degradation of this protein in these cells. Prokineticin-2 induced the formation of vessel-like structures by human aortic endothelial cells expressing only PKR1, and disorganized the tight junctions in human hepatic sinusoidal endothelial cells expressing only PKR2, confirming the divergent roles of these receptors. Our findings show the functional characteristics of coronary endothelial cells depend on the expression of PKR1 and PKR2 levels and the divergent signaling pathways used by these receptors.

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Sugimoto, Naotoshi, Noriko Takuwa, Hiroyuki Okamoto, Sotaro Sakurada, and Yoh Takuwa. "Inhibitory and Stimulatory Regulation of Rac and Cell Motility by the G12/13-Rho and Gi Pathways Integrated Downstream of a Single G Protein-Coupled Sphingosine-1-Phosphate Receptor Isoform." Molecular and Cellular Biology 23, no. 5 (March 1, 2003): 1534–45. http://dx.doi.org/10.1128/mcb.23.5.1534-1545.2003.

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ABSTRACT The G protein-coupled receptors S1P2/Edg5 and S1P3/Edg3 both mediate sphingosine-1-phosphate (S1P) stimulation of Rho, yet S1P2 but not S1P3 mediates downregulation of Rac activation, membrane ruffling, and cell migration in response to chemoattractants. Specific inhibition of endogenous Gα12 and Gα13, but not of Gαq, by expression of respective C-terminal peptides abolished S1P2-mediated inhibition of Rac, membrane ruffling, and migration, as well as stimulation of Rho and stress fiber formation. Fusion receptors comprising S1P2 and either Gα12 or Gα13, but not Gαq, mediated S1P stimulation of Rho and also inhibition of Rac and migration. Overexpression of Gαi, by contrast, specifically antagonized S1P2-mediated inhibition of Rac and migration. The S1P2 actions were mimicked by expression of V14Rho and were abolished by C3 toxin and N19Rho, but not Rho kinase inhibitors. In contrast to S1P2, S1P3 mediated S1P-directed, pertussis toxin-sensitive chemotaxis and Rac activation despite concurrent stimulation of Rho via G12/13. Upon inactivation of Gi by pertussis toxin, S1P3 mediated inhibition of Rac and migration just like S1P2. These results indicate that integration of counteracting signals from the Gi- and the G12/13-Rho pathways directs either positive or negative regulation of Rac, and thus cell migration, upon activation of a single S1P receptor isoform.

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Kitamura, Kenichiro, Naoki Shiraishi, William D. Singer, Mary E. Handlogten, Kimio Tomita, and R. Tyler Miller. "Endothelin-B receptors activate Gα13." American Journal of Physiology-Cell Physiology 276, no. 4 (April 1, 1999): C930—C937. http://dx.doi.org/10.1152/ajpcell.1999.276.4.c930.

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Endothelin (ET) receptors activate heterotrimeric G proteins that are members of the Gi, Gq, and Gs families but may also activate members of other families such as Gα12/13. Gα13 has multiple complex cellular effects that are similar to those of ET. We studied the ability of ET receptors to activate Gα13 using an assay for G protein α-chain activation that is based on the fact that an activated (GTP-bound) α-chain is resistant to trypsinization compared with an inactive (GDP-bound) α-chain. Nonhydrolyzable guanine nucleotides and AlMgF protected Gα13 from degradation by trypsin. In membranes from human embryonic kidney 293 cells that coexpress ETB receptors and α13, ET-3 and 5′-guanylylimidodiphosphate [Gpp(NH)p] increased the protection of α13 compared with Gpp(NH)p alone. The specificity of ETBreceptor-α13 coupling was documented by showing that β2receptors and isoproterenol or ETAreceptors and ET-1 did not activate α13 and that a specific antagonist for ETB receptors blocked ET-3-dependent activation of α13.

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Kurose, Hitoshi. "Gα12 and Gα13 as key regulatory mediator in signal transduction." Life Sciences 74, no. 2-3 (December 2003): 155–61. http://dx.doi.org/10.1016/j.lfs.2003.09.003.

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KELLEY, Grant G., Sarah E. REKS, and Alan V. SMRCKA. "Hormonal regulation of phospholipase Cepsilon through distinct and overlapping pathways involving G12 and Ras family G-proteins." Biochemical Journal 378, no. 1 (February 15, 2004): 129–39. http://dx.doi.org/10.1042/bj20031370.

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PLC∊ (phospholipase C∊) is a novel PLC that has a CDC25 guanine nucleotide exchange factor domain and two RA (Ras-association) domains of which the second (RA2) is critical for Ras activation of the enzyme. In the present studies, we examined hormonal stimulation to elucidate receptor-mediated pathways that functionally regulate PLC∊. We demonstrate that EGF (epidermal growth factor), a receptor tyrosine kinase agonist, and LPA (lysophosphatidic acid), S1P (sphingosine 1-phosphate) and thrombin, GPCR (G-protein-coupled receptor) agonists, stimulate PLC∊ overexpressed in COS-7 cells. EGF stimulated PLC∊ in an RA2-dependent manner through Ras and Rap. In contrast, LPA, S1P and thrombin stimulated PLC∊ by both RA2-independent and -dependent mechanisms. To determine the G-proteins that mediate the effects of these GPCR agonists, we co-expressed constitutively active G-proteins with PLC∊ and found that Gα12, Gα13, Rho, Rac and Ral stimulate PLC∊ in an RA2-independent manner; whereas TC21, Rap1A, Rap2A and Rap2B stimulate PLC∊ in an RA2-dependent manner similar to H-Ras. Of these G-proteins, we show that Gα12/Gα13 and Rap partly mediate the effects of LPA, S1P and thrombin to stimulate PLC∊. In addition, the stimulation by LPA and S1P is also partly sensitive to pertussis toxin. These studies demonstrate diverse hormonal regulation of PLC∊ by distinct and overlapping pathways.

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Sugino, Shigekazu, Mohamed Farrag, and Victor Ruiz-Velasco. "Gα14 subunit-mediated inhibition of voltage-gated Ca2+ and K+ channels via neurokinin-1 receptors in rat celiac-superior mesenteric ganglion neurons." Journal of Neurophysiology 115, no. 3 (March 1, 2016): 1577–86. http://dx.doi.org/10.1152/jn.00980.2015.

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The mechanisms by which G proteins modulate voltage-gated Ca2+ channel currents (CaV), particularly CaV2.2 and CaV2.3, are voltage dependent (VD) or voltage independent (VI). VD pathways are typically mediated by Gαi/o and GαS subfamilies. On the other hand, VI inhibition modulation is coupled to the Gαq subfamily and signaling pathways downstream of phospholipase C stimulation. In most studies, this latter pathway has been shown to be linked to Gαq and/or Gα11 protein subunits. However, there are no studies that have examined whether natively expressed Gα14 subunits (Gαq subfamily member) couple G protein-coupled receptors (GPCR) with CaV2.2 channels. We report that Gα14 subunits functionally couple the substance P (SP)/neurokinin-1 (NK-1) receptor pathway to CaV2.2 channels in acutely dissociated rat celiac-superior mesenteric ganglion (CSMG) neurons. Exposure of CSMG neurons to SP blocked the CaV2.2 currents in a predominantly VD manner that was pertussis toxin and cholera toxin resistant, as well as Gαq/11 independent. However, silencing Gα14 subunits significantly attenuated the SP-mediated Ca2+ current block. In another set of experiments, exposure of CSMG neurons to SP led to the inhibition of KCNQ K+ M-currents. The SP-mediated M-current block was significantly reduced in neurons transfected with Gα14 small-interference RNA. Finally, overexpression of the GTP-bound Gαq/11 binding protein RGS2 did not alter the block of M-currents by SP but significantly abolished the oxotremorine methiodide-mediated M-current inhibition. Taken together, these results provide evidence of a new Gα14-coupled signaling pathway that modulates CaV2.2 and M-currents via SP-stimulated NK-1 receptors in CSMG neurons.

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Gohla, Antje, Stefan Offermanns, Thomas M. Wilkie, and Günter Schultz. "Differential involvement of Gα12 and Gα13 in receptor-mediated stress fiber formation." Journal of Biological Chemistry 274, no. 36 (September 1999): 25958. http://dx.doi.org/10.1016/s0021-9258(19)55365-0.

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Yamazaki, Junya, Hironori Katoh, Yoshiaki Yamaguchi, and Manabu Negishi. "Two G12 family G proteins, Gα12 and Gα13, show different subcellular localization." Biochemical and Biophysical Research Communications 332, no. 3 (July 2005): 782–86. http://dx.doi.org/10.1016/j.bbrc.2005.05.023.

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Bhattacharyya, Raja, Jayashree Banerjee, Kamel Khalili, and Philip B. Wedegaertner. "Differences in Gα12- and Gα13-mediated plasma membrane recruitment of p115-RhoGEF." Cellular Signalling 21, no. 6 (June 2009): 996–1006. http://dx.doi.org/10.1016/j.cellsig.2009.02.010.

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Pauwels, P. J., and F. C. Colpaert. "Disparate ligand-mediated Ca2+ responses by wild-type, mutant Ser200 Ala and Ser204 Ala α2A -adrenoceptor : Gα15 fusion proteins: evidence for multiple ligand-activation binding sites." British Journal of Pharmacology 130, no. 7 (August 2000): 1505–12. http://dx.doi.org/10.1038/sj.bjp.0703455.

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Murthy, K. S., H. Zhou, J. R. Grider, and G. M. Makhlouf. "Sequential activation of heterotrimeric and monomeric G proteins mediates PLD activity in smooth muscle." American Journal of Physiology-Gastrointestinal and Liver Physiology 280, no. 3 (March 1, 2001): G381—G388. http://dx.doi.org/10.1152/ajpgi.2001.280.3.g381.

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The identity of G proteins mediating CCK-stimulated phospholipase D (PLD) activity was determined in intestinal smooth muscle cells. CCK-8 activated Gq/11, G13, and G12, and the monomeric G proteins Ras-homology protein (RhoA) and ADP ribosylation factor (ARF). Activation of RhoA, but not ARF, was mediated by G13 and inhibited by Gα13 antibody. CCK-stimulated PLD activity was partly mediated by RhoA and could be inhibited to the same extent (47 ± 2% to 53 ± 6%) by 1) a dominant negative RhoA mutant, 2) RhoA antibody or Gα13 antibody, and 3) Clostridium botulinum C3 exoenzyme. PLD activity was also inhibited by ARF antibody, and the effect was additive to that of RhoA antibody or C3 exoenzyme. PLD activity was inhibited by calphostin C, bisindolylmaleimide I, and a selective protein kinase C (PKC)-α inhibitor; the inhibition was additive to that of ARF and RhoA antibodies and C3 exoenzyme. In contrast, activated G12 was not coupled to RhoA or ARF, and Gα12 antibody augmented PLD activity. Thus agonist-stimulated PLD activity is mediated additively by G13-dependent RhoA and by ARF and PKC-α and is modulated by an inhibitory G12-dependent pathway.

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Lee, S. J., J. W. Yang, I. J. Cho, W. D. Kim, M. K. Cho, C. H. Lee, and S. G. Kim. "The gep oncogenes, Gα12 and Gα13, upregulate the transforming growth factor-β1 gene." Oncogene 28, no. 9 (January 19, 2009): 1230–40. http://dx.doi.org/10.1038/onc.2008.488.

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Yamaguchi, Yoshiaki, Hironori Katoh, Hidekazu Yasui, Junko Aoki, Kazuhiro Nakamura, and Manabu Negishi. "Gα12 and Gα13 Inhibit Ca2+ -Dependent Exocytosis Through Rho/Rho-Associated Kinase-Dependent Pathway." Journal of Neurochemistry 75, no. 2 (January 4, 2002): 708–17. http://dx.doi.org/10.1046/j.1471-4159.2000.0750708.x.

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Katoh, Hironori, Junko Aoki, Yoshiaki Yamaguchi, Yoshimi Kitano, Atsushi Ichikawa, and Manabu Negishi. "Constitutively Active Gα12, Gα13, and GαqInduce Rho-dependent Neurite Retraction through Different Signaling Pathways." Journal of Biological Chemistry 273, no. 44 (October 30, 1998): 28700–28707. http://dx.doi.org/10.1074/jbc.273.44.28700.

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Pestana, Manuel. "Interaction between Gα12 and Gα13 protein subunits and dopamine receptors in renal proximal tubules." Hypertension Research 34, no. 9 (September 2011): 987–88. http://dx.doi.org/10.1038/hr.2011.86.

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Kilts, Jason D., Shu S. Lin, James E. Lowe, and Madan M. Kwatra. "Selective Activation of Human Atrial Gα12 and Gα13 by Gαq-coupled Angiotensin and Endothelin Receptors." Journal of Cardiovascular Pharmacology 50, no. 3 (September 2007): 299–303. http://dx.doi.org/10.1097/fjc.0b013e3180a72632.

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Waheed, Abdul A., and Teresa L. Z. Jones. "Hsp90 Interactions and Acylation Target the G Protein Gα12 but Not Gα13 to Lipid Rafts." Journal of Biological Chemistry 277, no. 36 (July 12, 2002): 32409–12. http://dx.doi.org/10.1074/jbc.c200383200.

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Moers, Alexandra, Alexander Nürnberg, Sandra Goebbels, Nina Wettschureck, and Stefan Offermanns. "Gα12/Gα13 Deficiency Causes Localized Overmigration of Neurons in the Developing Cerebral and Cerebellar Cortices." Molecular and Cellular Biology 28, no. 5 (December 17, 2007): 1480–88. http://dx.doi.org/10.1128/mcb.00651-07.

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ABSTRACT The heterotrimeric G proteins G12 and G13 link G-protein-coupled receptors to the regulation of the actin cytoskeleton and the induction of actomyosin-based cellular contractility. Here we show that conditional ablation of the genes encoding the α-subunits of G12 and G13 in the nervous system results in neuronal ectopia of the cerebral and cerebellar cortices due to overmigration of cortical plate neurons and cerebellar Purkinje cells, respectively. The organization of the radial glia and the basal lamina was not disturbed, and the Cajal-Retzius cell layer had formed normally in mutant mice. Embryonic cortical neurons lacking G12/G13 were unable to retract their neurites in response to lysophosphatidic acid and sphingosine-1-phosphate, indicating that they had lost the ability to respond to repulsive mediators acting via G-protein-coupled receptors. Our data indicate that G12/G13-coupled receptors mediate stop signals and are required for the proper positioning of migrating cortical plate neurons and Purkinje cells during development.

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Orth, Joachim H. C., Inga Preuss, Ines Fester, Andreas Schlosser, Brenda A. Wilson, and Klaus Aktories. "Pasteurella multocidatoxin activation of heterotrimeric G proteins by deamidation." Proceedings of the National Academy of Sciences 106, no. 17 (April 15, 2009): 7179–84. http://dx.doi.org/10.1073/pnas.0900160106.

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Pasteurella multocidatoxin is a major virulence factor ofPasteurella multocida, which causes pasteurellosis in men and animals and atrophic rhinitis in rabbits and pigs. The ≈145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the Gαq, Gαi, and Gα12/13families by using an as yet unknown mechanism. Here, we show thatPasteurella multocidatoxin deamidates glutamine-205 of Gαi2to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of Gαiand causes persistent activation of the G protein. A similar modification is also evident for Gαq, but not for the closely related Gα11, which is not a substrate ofPasteurella multocidatoxin. Our data identify the α-subunits of heterotrimeric G proteins as the direct molecular target ofPasteurella multocidatoxin and indicate that the toxin does not act like a protease, which was suggested from its thiol protease-like catalytic triad, but instead causes constitutive activation of G proteins by deamidase activity.

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Yamaguchi, Yoshiaki, Hironori Katoh, Kazutoshi Mori, and Manabu Negishi. "Gα12 and Gα13 Interact with Ser/Thr Protein Phosphatase Type 5 and Stimulate Its Phosphatase Activity." Current Biology 12, no. 15 (August 2002): 1353–58. http://dx.doi.org/10.1016/s0960-9822(02)01034-5.

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Stemmle, Laura N., Timothy A. Fields, and Patrick J. Casey. "The Regulator of G Protein Signaling Domain of Axin Selectively Interacts with Gα12 but Not Gα13." Molecular Pharmacology 70, no. 4 (July 25, 2006): 1461–68. http://dx.doi.org/10.1124/mol.106.023705.

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Journal articles on the topic 'Gα15'

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