Gαq-coupled Receptor Internalization Specifically Induced by Gαq Signaling

In the present report, we investigated the effect of ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) expression on the agonist-induced internalization of the thromboxane A2 β receptor (TPβ receptor). Interestingly, we found that EBP50 almost completely blocked TPβ receptor internalization, which could not be reversed by overexpression of G protein-coupled receptor (GPCR) kinases and arrestins. Because we recently demonstrated that EBP50 can bind to and inhibit Gαq, we next studied whether Gαq signaling could induce TPβ receptor internalization, addressing the long standing question about the relationship between GPCR signaling and their internalization. Expression of a constitutively active Gαq mutant (Gαq-R183C) resulted in a robust internalization of the TPβ receptor, which was unaffected by expression of dominant negative mutants of arrestin-2 and -3, but inhibited by expression of EBP50 or dynamin-K44A, a dominant negative mutant of dynamin. Phospholipase Cβ and protein kinase C did not appear to significantly contribute to internalization of the TPβ receptor, suggesting that Gαq induces receptor internalization through a phospholipase Cβ- and protein kinase C-independent pathway. Surprisingly, there appears to be specificity in Gα protein-mediated GPCR internalization. Gαq-R183C also induced the internalization of CXCR4 (Gαq-coupled), whereas it failed to do so for the β2-adrenergic receptor (Gαs-coupled). Moreover, Gαs-R201C, a constitutively active form of Gαs, had no effect on internalization of the TPβ, CXCR4, and β2-adrenergic receptors. Thus, we showed that Gα protein signaling can lead to internalization of GPCRs, with specificity in both the Gα proteins and GPCRs that are involved. Furthermore, a new function has been described for EBP50 in its capacity to inhibit receptor endocytosis. In the present report, we investigated the effect of ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) expression on the agonist-induced internalization of the thromboxane A2 β receptor (TPβ receptor). Interestingly, we found that EBP50 almost completely blocked TPβ receptor internalization, which could not be reversed by overexpression of G protein-coupled receptor (GPCR) kinases and arrestins. Because we recently demonstrated that EBP50 can bind to and inhibit Gαq, we next studied whether Gαq signaling could induce TPβ receptor internalization, addressing the long standing question about the relationship between GPCR signaling and their internalization. Expression of a constitutively active Gαq mutant (Gαq-R183C) resulted in a robust internalization of the TPβ receptor, which was unaffected by expression of dominant negative mutants of arrestin-2 and -3, but inhibited by expression of EBP50 or dynamin-K44A, a dominant negative mutant of dynamin. Phospholipase Cβ and protein kinase C did not appear to significantly contribute to internalization of the TPβ receptor, suggesting that Gαq induces receptor internalization through a phospholipase Cβ- and protein kinase C-independent pathway. Surprisingly, there appears to be specificity in Gα protein-mediated GPCR internalization. Gαq-R183C also induced the internalization of CXCR4 (Gαq-coupled), whereas it failed to do so for the β2-adrenergic receptor (Gαs-coupled). Moreover, Gαs-R201C, a constitutively active form of Gαs, had no effect on internalization of the TPβ, CXCR4, and β2-adrenergic receptors. Thus, we showed that Gα protein signaling can lead to internalization of GPCRs, with specificity in both the Gα proteins and GPCRs that are involved. Furthermore, a new function has been described for EBP50 in its capacity to inhibit receptor endocytosis. G protein-coupled receptor ezrin-radixin-moesin-binding phosphoprotein 50 ezrin-radixin-moesin G protein-coupled receptor kinase NHE regulatory factor phospholipase C thromboxane A2 receptor hemagglutinin protein kinase C enzyme-linked immunosorbent assay bovine serum albumin fluorescein isothiocyanate Tris-buffered saline dominant negative phosphate-buffered saline phorbol 12-myristate 13-acetate G protein-coupled receptor (GPCR)1 signaling cascades are regulated by different molecular mechanisms. Many proteins have been shown to regulate the different GPCR-related signaling pathways through the direct regulation of the G protein activity (1Hollinger S. Hepler J.R. Pharmacol. Rev. 2002; 54: 527-559Crossref PubMed Scopus (606) Google Scholar). Following agonist binding, many GPCRs undergo agonist-induced phosphorylation, internalization, and down-regulation, resulting in a decrease of their responsiveness (desensitization) (2Tsao P. Von Zastrow M. Trends Pharmacol. Sci. 2001; 22: 91-96Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). Our studies are mainly interested in the mechanisms that regulate the signaling and the internalization of the thromboxane A2 receptor (TP receptor). Two TP receptor isoforms were identified which are generated by the alternative splicing of a single gene, TPα (343 amino acids) and TPβ (407 amino acids), which share the first 328 amino acids (3Hirata M. Hayashi Y. Ushikubi F. Yokota Y. Kageyama R. Nakanishi S. Narumiya S. Nature. 1991; 349: 617-620Crossref PubMed Scopus (623) Google Scholar, 4Raychowdhury M.K. Yukawa M. Collins L.J. McGrail S.H. Kent K.C. Ware J.A. J. Biol. Chem. 1994; 269: 19256-19261Abstract Full Text PDF PubMed Google Scholar). Previous experiments performed by Parent et al. (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar) demonstrated that only TPβ, but not TPα, undergoes agonist-induced and tonic (constitutive) internalizations, which are dictated by distinct motifs in the C terminus of the TPβ receptor. Different experiments showed that agonist-induced production of the second messenger inositol phosphate by the TP receptors results from the activation of the Gq/11 family of the Gα subunits (6Kinsella B.T. Biochem. Soc. Trans. 2001; 29: 641-654Crossref PubMed Google Scholar). Gαq-mediated production of inositol phosphates involves the stimulation of phospholipase C-β (PLC-β) isoforms (7Smrcka A.V. Sternweis P.C. J. Biol. Chem. 1993; 268: 9667-9674Abstract Full Text PDF PubMed Google Scholar). More recently, we have shown that the ezrin-radixin-moesin-binding phosphoprotein EBP50 regulates the Gαq signaling pathway of the TP receptors (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). We showed that EBP50 binds preferentially to the active form of Gαq and thus diminishes the Gαq-induced inositol phosphates production on the one hand by inhibiting the interaction of the activated Gαqwith PLCβ-1, and on the other hand by preventing the coupling of the TP receptors to Gαq (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). EBP50 (also known as NHERF1), a 55-kDa phosphoprotein, was first identified as a cofactor essential for protein kinase A-mediated of Y. S. J. PubMed Scopus Google Scholar). EBP50 and in and which binds to the proteins and C. C. F. J. V. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google M. J. Biol. PubMed Scopus Google Scholar). EBP50 has been found to with a of and are in a of the of signaling receptor and of proteins to the S. J. 2001; PubMed Google Scholar). In al. Zastrow Nature. 1999; PubMed Scopus Google Scholar) have shown that EBP50 in GPCR by its in the to the of the β2-adrenergic receptor its agonist-induced internalization. there no that EBP50 can regulate the internalization of has long been that to GPCRs the to their internalization and studies about a new of the regulation of GPCRs internalization pathways by signaling cascades V. M. J. 2001; PubMed Scopus Google Scholar). In many signaling the G proteins and as as different have been shown to regulate the pathways by the or by as by et al. V. M. J. 2001; PubMed Scopus Google Scholar). of the in GPCR regulation whether GPCR signaling for GPCR internalization. the by that there no to that question and that it on the GPCR and the signaling pathways that are GPCR mutants to their G proteins could whereas the was also GPCRs were to undergo agonist-induced internalization S. P. J. 274: Google Scholar). In of the on the receptor signaling were for only one signaling pathway a GPCR can to one of Gα Moreover, different studies constitutively active GPCR mutants a between receptor signaling and internalization. many to of GPCRs by their expression resulting in their S. C. S. P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. P. Pharmacol. 2001; PubMed Scopus Google which can be reversed by the of agonist J. C. P. Pharmacol. 2001; PubMed Scopus Google Scholar). there of a between the signaling activity of GPCRs and their internalization, it not whether internalization the of activation of the signaling cascades or of the active by the constitutively active receptors. In other it not whether GPCR by the of the agonist are and to the internalization of different GPCRs or whether the activation of the signaling cascades in the internalization the other it has been shown that activation of protein kinase C results in the and internalization of the CXCR4 M.J. Parent J.L. Benovic J.L. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) and the receptors J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). studies that activation of signaling induces the internalization of there no or for the direct of Gα protein signaling in the of internalization In the present we that Gα protein signaling can induce GPCR internalization. In of almost completely blocked the agonist-induced internalization of the TPβ receptor. Surprisingly, we that there specificity in Gαq signaling to but not receptor internalization, whereas signaling not internalization of the GPCRs that we Gαq-mediated internalization was to by and but and was completely by Gαs, and were from was were from was from whereas the fluorescein isothiocyanate and were from and the were from were in with bovine serum in a of to were performed to the from the was to the on were of expression and internalization of CXCR4, TPβ, and were by experiments as we have described (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). were in were with or with or with or were as described for were to with and were for the agonist-induced or internalization, the were with phosphate-buffered saline by a stimulation with or in for the that were with the receptors described and were with for were with and blocked with for were with a or the a of in for with and were for with was for were with for were with and a was as by the resulting were a with were studied to experiments were in receptor mutant in internalization was with were in as described were with or with receptor mutant in and or and as described were on and were with for in with by a were with for with and with for was blocked with for was a of for were with with the for the were with as were and by on a a were and with of the TPβ receptor was as we described M.J. Parent J.L. Benovic J.L. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). were in as described and the with or with the were with and for in with were in the or of for by a stimulation with were with and in of 50 with and the were in for the were by for of were to the a with 50 of protein in was by with were for in a and with of proteins were by of 50 of by a were on were and to phosphate were performed as described 2002; PubMed Scopus Google Scholar). were in were as described with the were the for with in were in and in with and for were for with in the of the TP the was and the were by of of were in and of were and for in a phosphates were on inositol phosphates were by are as of were by for with to the We have shown that EBP50 TPβ signaling through the by both preventing the receptor coupling to by of Gαq it from and (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). We investigated the of EBP50 in the agonist-induced internalization of TPβ receptor by the of as we described (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). Surprisingly, we have found that EBP50 almost completely inhibited the agonist-induced internalization of the TPβ receptor, as shown in In EBP50 inhibited the internalization of the TPβ receptor the dominant negative mutant form of dynamin-K44A, which in and known to internalization of proteins Rev. Biol. PubMed Scopus Google Scholar). We had demonstrated that agonist-induced internalization of the TPβ receptor (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google and was thus as a to EBP50 has been shown to be in the of the of proteins as the β2-adrenergic receptors Zastrow Nature. 1999; PubMed Scopus Google Scholar) by their to the We were thus interested in whether the of TPβ receptor internalization in of EBP50 was not in by in receptor to the et al. Zastrow Nature. 1999; PubMed Scopus Google Scholar) have shown that the of EBP50 was for the of the β2-adrenergic receptor and that a dominant negative mutant of EBP50 the was to the of receptor. showed that the of EBP50 was also for the of the receptor C. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, we a the of EBP50 to its effect on TPβ receptor internalization. in we have found that EBP50 mutant to inhibit TPβ receptor internalization, suggesting that the of TPβ receptor internalization by EBP50 could not be by in the of the TPβ receptor. We the effect of EBP50 and its the on the agonist-induced internalization of the receptor to that EBP50 was in results showed in the of the agonist-induced internalization of the receptor by whereas of the the had no effect on receptor internalization not that the effect of EBP50 on the agonist-induced internalization of results from in its the as was shown by et al. Zastrow Nature. 1999; PubMed Scopus Google Scholar). Moreover, as we in of with had no effect on the EBP50 as on the of the agonist-induced TPβ receptor internalization. known to inhibit activity J.L. Full Text PDF PubMed Scopus Google and we have shown it to inhibit TPβ receptor in and J.-L. in so that EBP50 the TPβ receptor internalization, its to the that EBP50 the of TPβ receptor internalization, we performed In with or with and were with to internalization experiments to for of only the receptors that are from the as we described (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). agonist it can be in of the TPβ receptors are in In the in of EBP50 agonist and for the between and of receptor stimulation not that EBP50 TPβ receptor internalization. were in of the known of EBP50 in receptor and of proteins to the it has been shown that EBP50 can inhibit the internalization of a we were interested in the in the of the TPβ receptor internalization by Because we showed that the EBP50 of the TPβ receptor internalization did not the of the TPβ receptor we investigated the effect of EBP50 on the known to in GPCR internalization. We demonstrated that the agonist-induced internalization of the TPβ receptor as as (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). we performed TPβ receptors with and both and or that of TPβ receptors undergo agonist-induced internalization the are with of and in the of EBP50 TPβ receptor internalization to and results were for and (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). the first regulation of the TPβ receptor by and thus the TPβ receptor as a for also that EBP50 of TPβ receptor internalization could not be reversed by overexpression of or of arrestin-2 also failed to the by EBP50 not that EBP50 through a other the and internalization pathway. we have recently shown that EBP50 with the TPβ receptor signaling through the Gαq pathway (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). EBP50 the interaction of proteins with the its M. J. Biol. PubMed Scopus Google Scholar). the not in the regulation of Gαq the and the and of EBP50 are for Gαq and the of Gαq-mediated signaling (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). Interestingly, the and the and of EBP50 are not only but are the of TPβ receptor internalization to the of in the regulation of the TPβ receptor internalization. Surprisingly, we have found that TPβ with a constitutively active Gαq mutant (Gαq-R183C) a of TPβ receptor expression the In of TPβ expression was Gαq-R183C was with TPβ with Moreover, of TPβ receptor expression the was to the of not Interestingly, the of TPβ receptor expression induced by Gαq-R183C was by the of the agonist-induced internalization of the TPβ receptor as as the internalization of GPCRs Rev. Biol. PubMed Scopus Google Scholar). Thus, it appears that the expression of the TPβ receptors in of Gαq-R183C the of internalization Because EBP50 binds preventing it from Gαq signaling (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google we investigated the effect of EBP50 on the internalization of TPβ receptors. We a of expression of TPβ receptors in with and in to with and that EBP50 the internalization of the TPβ receptor. that Gαq-R183C induces internalization of the TPβ receptor, we performed experiments with and Gαq-R183C or TPβ receptor internalization, and its the of the results in we are of the which in internalization J.L. Labrecque P. M.D. Benovic J.L. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). were with for to internalization experiments to the receptors from the as described for were to to internalization to and the receptors by with a that only the that were with both and whereas the the in with and that Gαq-R183C induces internalization of TPβ as was in with the the of internalization of the TPβ receptor by the of the of from the Rev. Biol. PubMed Scopus Google the of TPβ receptor internalization by EBP50 the of its capacity to with Gαq results that Gαq-mediated signaling in TPβ internalization, on one hand Gαq-R183C to induce TPβ receptor internalization and on the other hand TPβ receptor agonist activation results mainly in the activation of the Gαq pathway (6Kinsella B.T. Biochem. Soc. Trans. 2001; 29: 641-654Crossref PubMed Google Scholar). Furthermore, which the activation of the Gαq signaling also to inhibit both the and internalization of TPβ that activation of Gαq in the internalization Gαq activation induces inositol phosphate production by isoforms to activation of which the of a of 2002; PubMed Scopus Google Scholar). We next studied the of Gαq-mediated activation of and in TPβ receptor internalization. Interestingly, we have found that TPβ receptors undergo internalization in with and internalization of TPβ receptors was inhibited by the expression of expression of EBP50 did not the TPβ receptor internalization In was we showed EBP50 to bind and inhibit Gαq, which of and thus have no effect on direct activation of by (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). of EBP50 to internalization of TPβ receptors that it not with the internalization that EBP50 of agonist-induced internalization of TPβ receptor a of its direct of Gαq also that as as induced activation of could be in internalization of the TPβ receptor. activation and activation of are known to the and internalization of both and CXCR4 receptors M.J. Parent J.L. Benovic J.L. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). whether activation in TPβ receptor internalization, we the effect of the in that TPβ receptor agonist-induced internalization was inhibited of with of by was by a receptor with or were with and to experiments with a for in or of can be of the a of TPβ receptor, whereas of with completely the of the receptor, that was inhibited in Thus, it that activation of not a in the of the agonist-induced internalization of the TPβ receptor. Moreover, internalization was not with not of activation in the regulation of the internalization of the TPβ receptor was We have found that of with a could not the agonist-induced internalization of the TPβ receptor whereas it TPβ inositol phosphate production by Thus, it appears that activation also not a in the TPβ receptor internalization results that internalization of TPβ receptor on Gαq signaling direct of Gαq by EBP50 completely both and internalization, but that there are mechanisms other and pathways involved. In it to that Gαq and receptors were recently shown to and its signaling of second production Biol. 2002; 22: PubMed Scopus Google Scholar, H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, signaling pathways are known to be in the regulation of as by et al. V. M. J. 2001; PubMed Scopus Google Scholar). in results the first for a direct regulation of receptor internalization by a to the specificity or of Gα protein signaling in GPCR internalization, we performed experiments to the effect of a constitutively active mutant on the expression of TPβ receptors. that of TPβ receptor with did not the expression of TPβ receptors in to the expression in TPβ receptor of the protein was in by not of Gαq-R183C with the TPβ receptor was to induce a decrease in its to Gαq pathways do not regulate the internalization of the TPβ receptor. Thus, a specificity in Gαq-mediated internalization of the TPβ receptor to which receptor also known to to B.T. Biochem. Soc. Trans. 2001; 29: 641-654Crossref PubMed Google and not effect of Gαq signaling on the regulation of the internalization of CXCR4 receptor, receptor, was We performed experiments with and or Interestingly, we a decrease in the expression of in Gαq-R183C with the with results that a direct activation of Gαq signaling by expression of Gαq-R183C in internalization of both TPβ and CXCR4 both receptors. as it that activation of Gαq signaling could in the internalization of receptors we only receptors in experiments to be to to other receptors. the specificity of internalization, we performed experiments with and or that Gαq-R183C did not the expression of the in to with and Because a receptor, we the effect of the constitutively active mutant on the expression of results shown in that expression did not induce internalization of the but that it for which we have no that Gαq-R183C induce internalization of the to the internalization of GPCRs, which are to of other GPCRs and active Gα proteins to the specificity of internalization of GPCRs We demonstrated that Gαq-R183C signaling induces internalization of both TPβ and CXCR4 receptors. Because internalization of TPβ (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google we investigated the effect of and F. Benovic J.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, M.J. Benovic J.L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) dominant negative mutants on internalization of the TPβ receptor. experiments were performed with and or with both and and or that the internalization of the TPβ receptor could not be by of both and results from and that internalization of the TPβ receptor by GPCR involves molecular mechanisms that can be or not Pharmacol. Rev. 2001; Google Scholar). Our results also that both and pathways could be activated agonist stimulation of the TPβ receptor. we in a that the agonist-induced internalization of the TPβ receptor was only inhibited by by expression of dominant negative mutants (5Parent J.L. Labrecque P. Orsini M.J. Benovic J.L. J. Biol. Chem. 1999; 274: 8941-8948Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar). We the that there could be alternative for TPβ receptor the pathway. In the present we of the to that question by that Gαq signaling in the internalization of the TPβ receptor in results of a new in Gαq-mediated internalization of receptors. also the question whether activation of the Gαq signaling pathway by receptor could the internalization of receptor present the In to we performed with and or We that stimulation of the with the TP agonist results in a of CXCR4 receptors was only in both TPβ and CXCR4 but not in the CXCR4 that activation of the TPβ receptor results in internalization of the CXCR4 receptor. was but also as we have shown that the internalization of both the TPβ and CXCR4 receptors could be induced by Interestingly, with internalization of CXCR4 induced by stimulation of the TPβ receptor was inhibited by of EBP50 activation of the Gαq signaling pathway by agonist stimulation of the TPβ receptor can induce the internalization of the CXCR4 receptor, receptor. In the present we new to the question which has been for a long Gα protein signaling in internalization of Our results that Gα protein signaling can GPCR we showed that Gαq signaling can induce internalization of specificity in the Gα protein that can GPCR internalization, as by the that could not induce internalization of the receptors in We demonstrated that the Gαq-mediated internalization specificity for internalization was not induced by Gαq We that the Gαq-induced internalization was and a GPCR internalization that has been Gαq signaling to GPCR internalization could be the Gαq-mediated activation of pathways Biol. 2002; 22: PubMed Scopus Google Scholar, H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, H. J. H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google which are known to in the and to regulate V. M. J. 2001; PubMed Scopus Google Scholar). Interestingly, the TP receptor was recently shown to S. H. Y. J. 2001; PubMed Google Scholar). as to in Gαq signaling was of of the receptor, only GPCRs were induced to that are in the by the in the Gαq-mediated internalization, which the of in that EBP50 inhibited the TPβ receptor internalization. of receptor a function that has been described for of and could not the EBP50 of TPβ receptor internalization, that EBP50 not EBP50 TPβ receptor internalization by to by a we that EBP50 binds Gαq and TPβ receptor pathways (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). EBP50 the but not the internalization of the TPβ receptor. of the bind of EBP50 inhibited receptor internalization, suggesting that the of a by EBP50 not but that of Gαq for of TPβ receptor endocytosis. of in Our was performed in a proteins were We have the specificity of the interaction between Gαq and the of EBP50 (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). that EBP50 internalization of the receptor the that EBP50 not in the of internalization. Furthermore, other proteins that were of and do not bind Gαq (8Rochdi M.D. Watier V. La Madeleine C. Nakata H. Kozasa T. Parent J.-L. J. Biol. Chem. 2002; 277: 40751-40759Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) and do not TPβ receptor internalization not and of that Gαq signaling can lead to or internalization of GPCRs could in GPCRs whereas a could from of signaling we have no that the Gαq-mediated internalization in it to that receptors a undergo internalization Gαq activated by a to regulate as proteins or a of or of to be to the mechanisms and of Gα protein-mediated internalization of

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