Interaction between Pleckstrin Homology Domains and G Protein .BETA..GAMMA.-Subunits: Analyses of Kinetic Parameters by a Biosensor-Based Method.

Sawai, Tohru; Hirakawa, Tetsuya; Yamada, Koji; Nishizawa, Y

doi:10.1248/bpb.22.229

Cited by 9 publications

(6 citation statements)

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“…In the presence of Gαt, cimetidine-, ranitidine-and tiotidineinduced ERK1/2 phosphorylation was significantly inhibited ( Figure 9A). These results were confirmed by the PH domain of GRK2, another well-described scavenger of Gβγ [25,26] ( Figure 9B). Moreover, LY294002, an inhibitor of PI3K, also blocked cimetidine-, ranitidine-and tiotidine-induced ERK1/2 phosphorylation ( Figure 9C).…”

Section: Figure 6 Characterization Of H 2 R Desensitization Promoted supporting

confidence: 63%

Signal transduction mechanism of biased ligands at histamine H2 receptors

Alonso

Monczor

Echeverría

et al. 2014

Biochemical Journal

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7TMRs (seven-transmembrane receptors) exist as conformational collections in which different conformations would lead to differential downstream behaviours such as receptor phosphorylation, G-protein activation and receptor internalization. In this context, a ligand may cause differential activation of some, but not all, of the signalling events, which are associated to a particular receptor, and it would lead to biased agonism. The aim of the present study was to investigate whether H2R (histamine H2 receptor) ligands, described as inverse agonists because of their negative efficacy at modulating adenylate cyclase, could display some positive efficacy concerning receptor desensitization, internalization or even signalling through an adenylate-cyclase-independent pathway. Our present findings indicate that treatment with H2R inverse agonists leads to receptor internalization in HEK (human embryonic kidney)-293T transfected cells, by a mechanism mediated by arrestin and dynamin, but independent of GRK2 (G-protein-coupled receptor kinase 2)-mediated phosphorylation. On the other hand, we prove that two of the H2R inverse agonists tested, ranitidine and tiotidine, also induce receptor desensitization. Finally, we show that these ligands are able to display positive efficacy towards the ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway by a mechanism that involves Gβγ and PI3K (phosphoinositide 3-kinase)-mediated signalling in both transfected HEK-293T cells and human gastric adenocarcinoma cells. These results point to the aspect of pluridimensional efficacy at H2R as a phenomenon that could be extended to naïve cells, and challenge previous classification of pharmacologically relevant histaminergic ligands.

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Section: Figure 6 Characterization Of H 2 R Desensitization Promoted supporting

confidence: 63%

Signal transduction mechanism of biased ligands at histamine H2 receptors

Alonso

Monczor

Echeverría

et al. 2014

Biochemical Journal

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“…Although it is unclear how Sos couples the µ‐opioid receptor to Rac‐dependent JNK activation, several reports provide a glimpse of the pathway. An interaction between the PH‐Sos and Gβ 1 γ 2 (Sawai et al . 1999) provides a possible means for Gβγ to regulate Sos activity.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol‐3 kinase is distinctively required for µ‐, but not κ‐opioid receptor‐induced activation of c‐Jun N‐terminal kinase

Kam

Chan

Wong

2004

Journal of Neurochemistry

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Opioid receptors are the therapeutic targets of narcotic analgesics. All three types of opioid receptors (l, d and j) are prototypical G i -coupled receptors with common signaling characteristics in their regulation of intracellular events. Nevertheless, numerous signaling processes are differentially regulated by the three receptors. We have recently demonstrated that stimulation of d-opioid receptor can up-regulate the activity of the c-Jun N-terminal kinase (JNK) in a pertussis toxin-sensitive manner (Kam et al. 2003; J. Neurochem. 84, 503-513). The present study revealed that the l-opioid receptor could stimulate JNK in both SH-SY5Y cells and transfected COS-7 cells. The mechanism by which the l-opioid receptor stimulated JNK was delineated with the use of specific inhibitors and dominant-negative mutants of signaling intermediates. Activation of JNK by the l-opioid receptor was mediated through Gbc, Src kinase, son-of-sevenless (Sos), Rac and Cdc42. Interestingly, unlike the d-opioid receptors, the l-opioid receptor required phosphatidylinositol-3 kinase (PI3K) to activate JNK. The l-opioid receptor-induced JNK activation was effectively inhibited by wortmannin or the coexpression of a dominant negative mutant of PI3Kc. Like the d-opioid receptor, activation of JNK by the j-opioid receptor occurred in a PI3K-independent manner. These studies revealed that the l-opioid receptor utilize a distinct mechanism to regulate JNK.

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“…A strong mechanistic consequence of the interaction between the PH domain of ␤-adrenergic receptor kinase 1 and G␤␥ has been defined (41,44). In contrast, G␤␥ has been demonstrated to bind a plethora of PH domains from diverse signaling molecules, including the PH domain of PLC-␤ (21,(45)(46)(47)(48); however, the functional significance of these interactions is still unclear.…”

Section: Discussionmentioning

confidence: 99%

The Pleckstrin Homology Domain of Phospholipase C-β2 as an Effector Site for Rac

Snyder

Singer

Wing

et al. 2003

Journal of Biological Chemistry

100

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Increasing evidence links the activation of Rho familyGTPases to the stimulation of lipid hydrolysis catalyzed by phospholipase C (PLC)-␤ isozymes. To better define this relationship, members of a library of recombinant Rho GTPases were screened for their capacity to directly engage various purified PLC-␤ isozymes. Of the 17 tested members of the Rho family, only the active isoforms of Rac (Rac1, Rac2, and Rac3) both stimulate PLC-␤ activity in vivo and bind PLC-␤ 2 and PLC-␤ 3 , but not PLC-␤ 1 , in vitro. Furthermore, the recognition site for Rac GTPases was localized to the pleckstrin homology (PH) domain of PLC-␤ 2 , and this PH domain is fully sufficient to selectively interact with the active versions of the Rac GTPases, but not with other similar Rho GTPases. Together, these findings present a quantitative evaluation of the direct interactions between Rac GTPases and PLC-␤ isozymes and define a novel role for the PH domain of PLC-␤ 2 as a putative effector site for Rac GTPases.

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Interaction between Pleckstrin Homology Domains and G Protein .BETA..GAMMA.-Subunits: Analyses of Kinetic Parameters by a Biosensor-Based Method.

Cited by 9 publications

References 0 publications

Signal transduction mechanism of biased ligands at histamine H2 receptors

Signal transduction mechanism of biased ligands at histamine H2 receptors

Phosphatidylinositol‐3 kinase is distinctively required for µ‐, but not κ‐opioid receptor‐induced activation of c‐Jun N‐terminal kinase

The Pleckstrin Homology Domain of Phospholipase C-β2 as an Effector Site for Rac

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