Regulation of GTP-binding Protein αq(Gαq) Signaling by the Ezrin-Radixin-Moesin-binding Phosphoprotein-50 (EBP50)

Although ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is a PDZ domain-containing protein known to bind to various channels, receptors, cytoskeletal elements, and cytoplasmic proteins, there is still very little evidence for a role of EBP50 in the regulation of receptor signal transduction. In this report, we show that EBP50 inhibits the phospholipase C (PLC)-β-mediated inositol phosphate production of a Gαq-coupled receptor as well as PLC-β activation by the constitutively active Gαq-R183C mutant. Coimmunoprecipitation experiments revealed that EBP50 interacts with Gαq and to a greater extent with Gαq-R183C. Agonist stimulation of the thromboxane A2 receptor (TP receptor) resulted in an increased interaction between EBP50 and Gαq, suggesting that EBP50 preferentially interacts with activated Gαq. We also demonstrate that EBP50 inhibits Gαq signaling by preventing the interaction between Gαq and the TP receptor and between activated Gαq and PLC-β1. Investigation of the EBP50 regions involved in Gαq binding indicated that its two PDZ domains are responsible for this interaction. This study constitutes the first demonstration of an interaction between a G protein α subunit and another protein through a PDZ domain, with broad implications in the regulation of diverse physiological systems. Although ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is a PDZ domain-containing protein known to bind to various channels, receptors, cytoskeletal elements, and cytoplasmic proteins, there is still very little evidence for a role of EBP50 in the regulation of receptor signal transduction. In this report, we show that EBP50 inhibits the phospholipase C (PLC)-β-mediated inositol phosphate production of a Gαq-coupled receptor as well as PLC-β activation by the constitutively active Gαq-R183C mutant. Coimmunoprecipitation experiments revealed that EBP50 interacts with Gαq and to a greater extent with Gαq-R183C. Agonist stimulation of the thromboxane A2 receptor (TP receptor) resulted in an increased interaction between EBP50 and Gαq, suggesting that EBP50 preferentially interacts with activated Gαq. We also demonstrate that EBP50 inhibits Gαq signaling by preventing the interaction between Gαq and the TP receptor and between activated Gαq and PLC-β1. Investigation of the EBP50 regions involved in Gαq binding indicated that its two PDZ domains are responsible for this interaction. This study constitutes the first demonstration of an interaction between a G protein α subunit and another protein through a PDZ domain, with broad implications in the regulation of diverse physiological systems. EBP50 1The abbreviations used are: EBP50, ezrin-radixin-moesin-binding phosphoprotein 50; ERM, ezrin-radixin-moesin; GAP, GTPase-activating protein; GPCR, G protein-coupled receptor; GRK, G protein-coupled receptor kinase; NHE3, Na+/H+ exchanger isoform 3; NHERF, NHE regulatory factor; PLC, phospholipase C; TP receptor, thromboxane A2 receptor; TXA2, thromboxane A2; CFTR, cystic fibrosis transmembrane conductance regulator; Ni-NTA, nickel-nitrilotriacetic acid; HA, hemagglutinin; RGS, regulators of G protein signaling. (also known as NHERF1), a 55-kDa phosphoprotein, was first identified as a cofactor essential for protein kinase A-mediated inhibition of Na+/H+ exchanger isoform 3 (NHE3) (1Weinman E.J. Steplock D. Wang Y. Shenolikar S. J. Clin. Invest. 1995; 95: 2143-2149Google Scholar). EBP50 contains two PDZ domains (PDZ1 and PDZ2) implicated in multiple protein-protein interactions, and an ERM domain, which binds to the actin-associated ERM proteins (ezrin, radixin, moesin, and merlin) (2Murthy A. Gonzalez-Agosti C. Cordero E. Pinney D. Candia C. Solomon F. Gusella J. Ramesh V. J. Biol. Chem. 1998; 273: 1273-1276Google Scholar,3Reczek D. Berryman M. Bretscher A. J. Cell Biol. 1997; 139: 169-179Google Scholar). EBP50 was also found to interact with a small number of transmembrane proteins such as the cystic fibrosis transmembrane conductance regulator (CFTR) (4Moyer B.D. Duhaime M. Shaw C. Denton J. Reynolds D. Karlson K.H. Pfeiffer J. Wang S. Mickle J.E. Milewski M. Cutting G.R. Guggino W.B., Li., M. Stanton B.A. J. Biol. Chem. 2000; 275: 27069-27074Google Scholar), the P2Y1 purinergic receptor (5Hall R.A. Ostedgaard L.S. Premont R.T. Blitzer J.T. Rahman N. Welsh M.J. Lefkowitz R.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 8496-8501Google Scholar), the platelet-derived growth factor receptor (6Maudsley S. Zamah A.M. Rahman N. Blitzer J.T. Luttrell L.M. Lefkowitz R.J. Hall R.A. Mol. Cell. Biol. 2000; 20: 8352-8363Google Scholar), the β2-adrenergic receptor (5Hall R.A. Ostedgaard L.S. Premont R.T. Blitzer J.T. Rahman N. Welsh M.J. Lefkowitz R.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 8496-8501Google Scholar), the B1 subunit of the H+-ATPase (7Breton S. Wiederhold T. Marshansky V. Nsumu N.N. Ramesh V. Brown D. J. Biol. Chem. 2000; 275: 18219-18224Google Scholar), and the type IIa sodium phosphate cotransporter (8Gisler S.M. Stagljar I. Traebert M. Bacic D. Biber J. Murer H. J. Biol. Chem. 2001; 276: 9206-9213Google Scholar). EBP50 also associates with the phospholipases C (PLC)-β1/β2, and with the TRP4 and TRP5 calcium channels to form a PLC-β1/2-TRP4/5-EBP50 protein complex (9Tang Y. Tang J. Chen Z. Trost C. Flockerzi V., Li, M. Ramesh V. Zhu M.X. J. Biol. Chem. 2000; 275: 37559-37564Google Scholar). The physiological role of this interaction on the regulation of PLC-β1/2 remains undefined. The EBP50 protein can also bind through its PDZ domains to various intracellular proteins, including GRK6A (10Hall R.A. Spurney R.F. Premont R.T. Rahman N. Blitzer J.T. Pitcher J.A. Lefkowitz R.J. J. Biol. Chem. 1999; 274: 24328-24334Google Scholar), EPI64 (11Reczek D. Bretscher A. J. Cell Biol. 2001; 153: 191-206Google Scholar), and Yes-associated protein 65 (12). A close relative of EBP50 has been identified and is known as E3KARP (13Yun C.H., Oh, S. Zizak M. Steplock D. Tsao S. Tse C.M. Weinman E.J. Donowitz M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3010-3015Google Scholar), SIP-1 (14Poulat F. Barbara P.S. Desclozeaux M. Soullierk S. Moniotk B. Bonneaudk N. Boizetk B. Berta P. J. Biol. Chem. 1997; 272: 7167-7172Google Scholar), and NHERF2 (15Hwang J.I. Heo K. Shin K.J. Kim E. Yun C. Ryu S.H. Shin H.S. Suh P.G. J. Biol. Chem. 2000; 275: 16632-16637Google Scholar). EBP50 and NHERF2 share 52% amino acid identity and a conserved domain architecture (13Yun C.H., Oh, S. Zizak M. Steplock D. Tsao S. Tse C.M. Weinman E.J. Donowitz M. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3010-3015Google Scholar). It has been shown recently that the PDZ domains of EBP50 can homo-oligomerize and also hetero-oligomerize with the PDZ domains of NHERF2 (16Lau A.G. Hall R.A. Biochemistry. 2001; 40: 8572-8580Google Scholar). Despite the growing evidence suggesting the role of EBP50 as a scaffolding protein involved in the formation of signaling complexes, there is still little evidence for a role of EBP50 in the regulation of transmembrane receptor signaling pathways. Our laboratory has been interested in the regulation of the thromboxane A2 (TXA2) receptors (TP receptors). TXA2 has a variety of pharmacological effects that modulate the physiological responses of several cells and tissues (17Kinsella B.T. Biochem. Soc. Trans. 2001; 29: 641-654Google Scholar). Binding of TXA2 to its receptor induces platelet aggregation, constriction of vascular and bronchiolar smooth muscle cells, as well as mitogenesis and hypertrophy of vascular smooth muscle cells (18Narumiya S. Sugimoto Y. Ushikubi F. Physiol. Rev. 1999; 79: 1193-1226Google Scholar). The TP receptor is part of the G protein-coupled receptor (GPCR) superfamily. Two TP receptor isoforms were identified that 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 (19Hirata M. Hayashi Y. Ushikubi F. Yokota Y. Kageyama R. Nakanishi S. Narumiya S. Nature. 1991; 349: 617-620Google Scholar, 20Raychowdhury M.K. Yukawa M. Collins L.J. McGrail S.H. Kent K.C. Ware J.A. J. Biol. Chem. 1994; 269: 19256-19261Google Scholar). Different experiments demonstrated that agonist-induced production of the second messenger inositol phosphates by the TP receptors results from the activation of the Gq/11 family of the Gα subunits (17Kinsella B.T. Biochem. Soc. Trans. 2001; 29: 641-654Google Scholar). Gαq-mediated production of inositol phosphates involves the stimulation of PLC-β isoforms in the following order of potency: PLC-β1 ≥ PLC-β3 > PLC-β2 (21Smrcka A.V. Sternweis P.C. J. Biol. Chem. 1993; 268: 9667-9674Google Scholar). Furthermore, PLC-β isoenzymes accelerate the intrinsic GTP hydrolysis by Gα subunits acting as a GTPase-activating protein (GAP) (22Chidiac P. Ross E.M. J. Biol. Chem. 1999; 274: 19639-19643Google Scholar). More recently, it was shown that PLC-βs form dimers in vivo and suggested that dimerization could mediate their interaction with GTP-bound Gαq (23Singer A.U. Waldo G.L. Harden T.K. Sondek J. Nat. Struct. Biol. 2002; 9: 32-36Google Scholar). Although the signaling pathways of the TP receptors are being described in increasing detail, their regulation remains to be characterized. Knowing that the TP receptor signaling cascade involves the activation of Gαq and the stimulation of the downstream effector PLC-β, we investigated the effect of EBP50 on the signaling of the agonist-stimulated TP receptor through the Gαq pathway. Surprisingly, our experiments revealed that EBP50 regulates the Gαq signaling pathway by preferentially binding through its PDZ domains to the activated Gαq and by preventing its interaction with PLC-β. Furthermore, we show that EBP50 also interferes in the TP receptor-Gαq coupling. This novel interaction between PDZ domains and Gαq has broad implications in intracellular signaling regulation. Growing evidence demonstrates the role of EBP50 in a wide variety of physiological events. The regulation of these events could possibly be modulated by the Gαq-EBP50 interaction. The Myc, Gαq/11, and PLCβ1-specific polyclonal antibodies were from Santa Cruz Biotechnology. Myc-specific monoclonal antibody was a gift from Dr. J. Stankova (Université de Sherbrooke). Hemagglutinin (HA)-specific monoclonal antibody was from Babco, and EBP50-specific monoclonal antibody was from BD Biosciences. ECL reagents were purchased fromAmersham Biosciences. Protein A-agarose and FuGENE 6TM were purchased from Roche Molecular Biochemicals. HEK293 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum at 37 °C in a humidified atmosphere containing 5% CO2. Transient transfections of HEK293 cells grown to 75–90% confluence were performed using FuGENE 6TMaccording to the manufacturer's instructions. Empty pcDNA3 vector was added to keep the total DNA amount added per plate constant. 6-Well plates of HEK293 cells were with and in the indicated the cells were maintained as described for The cells with TPα TPβ were for at 37 °C in the the of to The cells were with and in of 50 supplemented with and the cells were in for at the were by for at at to of monoclonal polyclonal antibodies were added to the of at 50 of protein A-agarose in was by an at were for in a and with of proteins were by of 50 of by a at and proteins were by and using phosphates were performed as described P. M.J. J. Biol. Chem. 1999; 274: Scholar). HEK293 cells were grown in The cells were as described with the indicated The cells were the following for with of in Dulbecco's modified Eagle's medium The cells were in and in Dulbecco's modified Eagle's medium supplemented with bovine serum and for were for with in the of the TP the medium was and the were by of of were in and of were and for at in a phosphates were on inositol phosphates were by The was a gift of Dr. of The domains of EBP50 ERM, and were by the of using the Molecular in the pcDNA3 and the of the was by for EBP50 was in the A vector and the was used to a EBP50 in by following the manufacturer's The EBP50 was using the as indicated by the The EBP50 was by and was by using an EBP50-specific monoclonal antibody as described The EBP50 was used in the Gαq interaction and The binding was performed using EBP50 as described was for at with of in binding 5% the was with the binding The EBP50 was for at °C with from HEK293 cells with with pcDNA3 in binding The binding were with binding was added to the binding and the were for The binding were by and using the indicated Gα was in using a single as described T. M.J. Sternweis A.G. Sternweis P.C. 1998; Scholar). of Gαq-R183C in the of the Gαq-R183C was in was in the the of EBP50 EBP50 were with of 5% A in 50 The was and was the effect of EBP50 on we total inositol phosphate production in HEK293 cells with with an pcDNA3 vector EBP50 following a TP receptor has been shown to the inositol phosphate of TP receptor isoforms Sternweis A.G. T. J. Biol. Chem. 1999; 274: and was in these experiments as a A that EBP50 results in a in the agonist-induced inositol phosphate production by TPα and and of their was to be of of protein for shown in A. the TP receptors PLC-β through the Gαq we at EBP50 could Gαq signaling. a Gαq that to the activation of PLC-β J. Biol. Chem. Scholar), was with an pcDNA3 vector EBP50, in HEK293 Although it was shown that Gαq-R183C activation of PLC-β, and on the such effect Sternweis A.G. T. J. Biol. Chem. 1999; 274: Scholar). and were used as Surprisingly, EBP50 inhibits the inositol phosphate production by activation of PLC-β. we a of of the inositol phosphate production Gαq-R183C was with EBP50 as with its with an vector results that EBP50 the inhibition of the production of inositol phosphates following TPα and TPβ stimulation by preventing the Gαq from PLC-β. EBP50 is a containing protein known for its to bind to a wide variety of We were interested in EBP50 could interact with Gαq. experiments were performed in HEK293 cells with and Gαq, Cell were with a polyclonal of the with an monoclonal antibody revealed that could be with Gαq and Gαq-R183C. the amount of that with Gαq-R183C was greater with Gαq The of a in of Gαq that Gαq proteins are for of results of the with the antibody that were in the cells with The Gαq-EBP50 interaction was in with an EBP50-specific and the was with the antibody to the Gαq it can be Gαq-R183C and Gαq could be with from Gαq-R183C with EBP50 in a amount the type Gαq. The of EBP50 in the was by using an EBP50-specific monoclonal antibody The interaction was by HEK293 Gαq-R183C protein to a The of that Gαq-R183C binds to EBP50, it bind to the Furthermore, binding was from HEK293 with pcDNA3 were of 3 of the binding with monoclonal of Gαq-R183C with of the protein and the binding were as described The that Gαq-R183C binds to the the the amount of protein in The results described in that EBP50 preferentially with Gαq-R183C constitutively active form of it with Gαq our that the interaction of EBP50 with the activated form of Gαq could be implicated in the to the inhibition of the agonist-induced inositol phosphate production by experiments were performed using HEK293 cells with and The cells were with the TP receptor for from to Cell were with the and the were by with the monoclonal shown in a small amount of EBP50 could be with Gαq in the of TPβ with results in A. a greater amount of EBP50 could be with Gαq a TPβ suggesting that the resulted in the activation of Gαq to an increased interaction with EBP50 of EBP50 with Gαq TPβ was for suggesting an of GTP-bound Gαq and a of Gαq-EBP50 interaction. Our that activation of Gαq by a results in a increased Gαq-EBP50 interaction. activation of by the TP and β2-adrenergic receptors that this Gα protein subunit could also bind to EBP50 Gα proteins and to interact with EBP50 in our and in a in the EBP50 interaction with Gα EBP50 with Gαq, we investigated the effect of EBP50 on the interaction. HEK293 cells were with of and pcDNA3 as described in The cells were with for and the were with a Myc-specific monoclonal of the with the polyclonal antibody revealed in the of EBP50 Gαq with TPα and TPβ of the receptors to Gαq stimulation of the amount of Gαq to the activation and the of Gαq. This was in a extent for the TPα for to Gαq. This is TPα and TPβ are also to regulation of events such as (17Kinsella B.T. Biochem. Soc. Trans. 2001; 29: 641-654Google and agonist-induced P. M.J. J. Biol. Chem. 1999; 274: Scholar, P. J. Biol. Chem. 2001; 276: Scholar). in the HEK293 cells with TPβ TPα with Gαq and EBP50, EBP50 to the of receptors to Gαq, we a in the amount of Gαq that could be with the effect of EBP50 on TPβ to Gαq was on the TPα to Gαq. it that EBP50 interferes in the It is well known that the GTP-bound form of Gαq the phospholipase of PLC-β1 by binding to its domain T. S. J.T. E. M.J. S. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar). In order to the interaction results in a of the activated Gαq, preventing it from the downstream such as we performed experiments of PLC-β1 in HEK293 cells with and an The were with a polyclonal of the with a antibody revealed that a amount of Gαq-R183C could be with PLC-β1 in the of EBP50 we these that Gαq-R183C interacts with PLC-β1 in the inositol phosphate production shown in B. The interaction between Gαq-R183C and PLC-β1 was was This demonstrates that EBP50 interferes with the activation of PLC-β1 by preventing the GTP-bound interaction. It can also be that and the form of Gαq, could bind to PLC-β1 demonstrates that EBP50 also binds to as was recently shown by Tang (9Tang Y. Tang J. Chen Z. Trost C. Flockerzi V., Li, M. Ramesh V. Zhu M.X. J. Biol. Chem. 2000; 275: 37559-37564Google Scholar). We were interested in the EBP50 domains involved in the interaction with activated Gαq. Different of EBP50 were as in A. HEK293 cells were with and of the indicated EBP50 Cell were with the and the were by with an monoclonal The results shown that the ERM domain with Gαq-R183C the and with that these domains are implicated in the interaction. the to in a greater amount PDZ domain (PDZ1 and PDZ2) the and to a as the EBP50 it that the domains are responsible for the interaction with activated Gαq. EBP50 is to be an for several proteins to the through its ERM domain, which is involved in the binding to the ERM The results described shown that the and domains are involved in the the ERM domain is we the ERM domain of EBP50 is for its inhibition of the Gαq binding to and the TP HEK293 cells were with and The were with a polyclonal The were by with the Surprisingly, the and domains the binding of Gαq-R183C to the ERM domain The effect of EBP50 domain on the interaction between TPβ and Gαq was HEK293 cells were with and The were with a Myc-specific monoclonal and the were by with the The results that EBP50, and could the of TPβ to Gαq, the ERM effect these results shown that the and the domains are to the of TPβ to Gαq as well as the binding of the activated Gαq to PLC-β1. we to EBP50 for Gαq. and GTP in the of activated is for GTP hydrolysis for Gαq of the single T. A.V. Sternweis P.C. A.G. J. Biol. Chem. 1993; 268: Scholar). the for GTP hydrolysis of Gαq-R183C is GTP to T. A.M. P. S. Ross E.M. A.G. J. 1998; Scholar). Furthermore, it was recently shown that the of Gαq-R183C can be by in a single T. A.M. P. S. Ross E.M. A.G. J. 1998; Scholar). we this to the of Gαq-R183C in the of Although GTP hydrolysis to of and EBP50 to GTP hydrolysis of it that EBP50 has to as a for Gαq. This study demonstrates a regulation of the Gαq signaling pathway by We shown that EBP50 the inositol phosphate production by TPα and TPβ We that EBP50 production of inositol phosphates by a constitutively active of Gαq. We demonstrated that EBP50 interacts in a greater extent with Gαq-R183C with Gαq. stimulation of the TPβ receptor the Gαq-EBP50 that EBP50 interacts with the activated Gαq. It was of stimulation of the amount of EBP50 that with Gαq to to was in the of It is known that the activation of Gαq by is a the of by Gαq and its for a hydrolysis of the GTP by the intrinsic of Gαq results in the of the Gαq subunit and its to the In of stimulation in their to G protein this could the of interaction stimulation of results that the regulation of the TP receptors signaling by EBP50 is by the binding of the activated Gαq to activation of the Gα subunit results in its from the the binding of the active form of Gαq to EBP50 could be to its from the subunits and to its GTP-bound active per the is the that the interact as well as Gαq-R183C with EBP50, the subunits can for the Furthermore, the activated Gαq-EBP50 interaction receptor stimulation is suggesting that the Gαq the EBP50 protein GTP which could that EBP50 binds preferentially to the active form of Gαq. More experiments to be performed to the subunits with EBP50 for the binding of Gαq. Our results that EBP50 interferes with the of the TP receptors to Gαq which could be by the binding of EBP50 to the active and the of to the of Gαq. It can be that EBP50 could also bind to the receptor, as for (5Hall R.A. Ostedgaard L.S. Premont R.T. Blitzer J.T. Rahman N. Welsh M.J. Lefkowitz R.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 8496-8501Google Scholar), and in the this The receptor interaction is in our GTP-bound Gαq preferentially PLC-β1 as described in the (23Singer A.U. Waldo G.L. Harden T.K. Sondek J. Nat. Struct. Biol. 2002; 9: 32-36Google shown that the GTP binds and PLC-β. on the EBP50 the inositol phosphate production and on the a greater for the active form of Gαq, the effect of EBP50 on the interaction was We an inhibition in the interaction of Gαq-R183C with PLC-β1 in the of the results described that EBP50 regulates the TP receptor signaling through Gαq at we shown that EBP50 interferes with the of the TP receptors to Gαq by binding and preventing the Gαq from binding to the TP we shown that EBP50 also interferes with the of the activated Gαq to the downstream effector PLC-β1. the G protein signaling by increasing the of GTP hydrolysis by Gα subunits to proteins of G protein and G protein as PLC-β and which an to the family of proteins bind the GTP-bound Gα subunits and share an domain involved in the regulation of the intrinsic of our results shown that EBP50 binds preferentially the GTP-bound Gαq, and that this interaction is activation of a GPCR, there was the that EBP50 could modulate the intrinsic GTP hydrolysis of Gαq. of the EBP50 amino acid and its with the proteins to show that EBP50 an Our results that EBP50 modulate the intrinsic of Gαq. of Gαq signaling by EBP50 on the We the of it was shown that the is in the of an activated Sternweis A.G. T. J. Biol. Chem. 1999; 274: Scholar), which the that receptors could a role in in it has been demonstrated that the of to Gαq-mediated in cells is on the of the receptors that are being S. K. D. S. S. J. Biol. Chem. 1999; 274: Scholar). The of this study suggested that regulatory be by of the role of receptors in EBP50 binds to and is involved in its regulation by as well as in its E.J. C. Shenolikar S. J. Physiol. 2000; Scholar). EBP50 also be to the H+-ATPase in and in cells E.J. C. Shenolikar S. J. Physiol. 2000; Scholar). Furthermore, EBP50 as a signal for B.D. Denton J. Karlson K.H. Reynolds D. Wang S. Mickle J.E. Milewski M. Cutting G.R. Guggino W.B., Li, M. Stanton B.A. J. Clin. Invest. 1999; and the dimerization of that the of V. Proc. Natl. Acad. Sci. U. S. A. 2001; Scholar). experiments (6Maudsley S. Zamah A.M. Rahman N. Blitzer J.T. Luttrell L.M. Lefkowitz R.J. Hall R.A. Mol. Cell. Biol. 2000; 20: 8352-8363Google shown that EBP50 is involved in the dimerization of the platelet-derived growth factor its EBP50 also regulates the of the β2-adrenergic receptor to pathways D. Bretscher A. Nature. 1999; Scholar). its EBP50 has been with a broad of of which on the interaction of EBP50 through its and domains with the Our study Gαq as a novel for the PDZ domains of This is in of G protein signaling regulation. The study of between PDZ domain-containing proteins with Gα subunits constitutes a and of It is also to the of the Gαq-EBP50 interaction in signaling an EBP50 to Gαq could possibly be to in the interaction with another binding can that multiple with EBP50 could be modulated by the activated Gαq-EBP50 interaction.

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