β1/β2-Adrenergic Receptor Heterodimerization Regulates β2-Adrenergic Receptor Internalization and ERK Signaling Efficacy

β1- and β2-adrenergic receptors (β1AR and β2AR) are co-expressed in numerous tissues where they play a central role in the responses of various organs to sympathetic stimulation. Although the two receptor subtypes share some signaling pathways, each has been shown to have specific signaling and regulatory properties. Given the recent recognition that many G protein-coupled receptors can form homo- and heterodimers, the present study was undertaken to determine whether the β1AR and β2AR can form dimers in cells and, if so, to investigate the potential functional consequences of such heterodimerization. Using co-immunoprecipitation and bioluminescence resonance energy transfer, we show that β1AR and β2AR can form heterodimers in HEK 293 cells co-expressing the two receptors. Functionally, β-adrenergic stimulated adenylyl cyclase activity was found to be identical in cells expressing β1AR, β2AR, or both receptors at similar levels, indicating that heterodimerization did not affect this signaling pathway. When considering ERK1/2 MAPK activity, a significant agonist-promoted activation was detected in β2AR- but not β1AR-expressing cells. Similarly to what was observed in cells expressing the β1AR alone, no β-adrenergic stimulated ERK1/2 phosphorylation was observed in cells co-expressing the two receptors. A similar inhibition of agonist-promoted internalization of the β2AR was observed upon co-expression of the β1AR, which by itself internalized to a lesser extent. Taken together, our data suggest that heterodimerization between β1AR and β2AR inhibits the agonist-promoted internalization of the β2AR and its ability to activate the ERK1/2 MAPK signaling pathway. β1- and β2-adrenergic receptors (β1AR and β2AR) are co-expressed in numerous tissues where they play a central role in the responses of various organs to sympathetic stimulation. Although the two receptor subtypes share some signaling pathways, each has been shown to have specific signaling and regulatory properties. Given the recent recognition that many G protein-coupled receptors can form homo- and heterodimers, the present study was undertaken to determine whether the β1AR and β2AR can form dimers in cells and, if so, to investigate the potential functional consequences of such heterodimerization. Using co-immunoprecipitation and bioluminescence resonance energy transfer, we show that β1AR and β2AR can form heterodimers in HEK 293 cells co-expressing the two receptors. Functionally, β-adrenergic stimulated adenylyl cyclase activity was found to be identical in cells expressing β1AR, β2AR, or both receptors at similar levels, indicating that heterodimerization did not affect this signaling pathway. When considering ERK1/2 MAPK activity, a significant agonist-promoted activation was detected in β2AR- but not β1AR-expressing cells. Similarly to what was observed in cells expressing the β1AR alone, no β-adrenergic stimulated ERK1/2 phosphorylation was observed in cells co-expressing the two receptors. A similar inhibition of agonist-promoted internalization of the β2AR was observed upon co-expression of the β1AR, which by itself internalized to a lesser extent. Taken together, our data suggest that heterodimerization between β1AR and β2AR inhibits the agonist-promoted internalization of the β2AR and its ability to activate the ERK1/2 MAPK signaling pathway. The standard model describing signaling in G protein-coupled receptors (GPCRs), 1The abbreviations used are: GPCR, G protein-coupled receptor; Rluc, Renillaluciferase; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; BRET, bioluminescence resonance energy transfer; HA, hemagglutinin; PBS, phosphate-buffered saline; GFP, green fluorescent protein; BSA, bovine serum albumin; βAR, β-adrenergic receptor; β1AR and β2AR, β1and β2-adrenergic receptor, respectively. where the receptor functions strictly as a monomer, is no longer tenable. In the past few years, a number of studies have demonstrated that oligomerization of GPCRs may play important roles in receptor trafficking and signaling (for reviews, see Refs. 1Bouvier M. Nat. Rev. Neurosci. 2001; 2: 274-286Crossref PubMed Scopus (582) Google Scholar and 2Angers S. Salahpour A. Bouvier M. Annu. Rev. Pharmacol. Toxicol. 2002; 42: 409-435Crossref PubMed Scopus (515) Google Scholar). 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Bouvier M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: Google Scholar, J. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). Although the two receptors more T. S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) and share as a T.E. S. C. Bouvier M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), no study has potential for heterodimerization. Although the two receptors are to to in functional have been the β2AR has been shown to be more some of the β1AR to adenylyl cyclase G. Bouvier M. Pharmacol. Google Scholar, S.A. Pharmacol. Google Scholar, L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). β2AR activation to a more of various MAPK signaling A. T. S. 2000; PubMed Scopus Google A. E. S.A. B.A. 2000; PubMed Scopus Google Scholar). In to the β2AR, which internalization the β1AR was found to at the for T. H. M. T. Bouvier M. Pharmacol. Google Scholar, T. T. H. Sci. 2001; PubMed Scopus Google Scholar, T. A. T. H. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). that for the they to the functional consequences of heterodimerization. In the present the occurrence of heterodimerization between the β1AR and β2AR was by co-immunoprecipitation and bioluminescence resonance energy in cells co-expressing the two receptors. The potential functional consequences of the heterodimerization by the of receptor co-expression the ability of the receptors to adenylyl cyclase and MAPK as as to agonist-promoted found that co-expression of the two receptor subtypes in HEK 293 cells to heterodimerization and both agonist-promoted β2AR internalization and ERK1/2 MAPK stimulation. that heterodimerization may a regulatory the of a receptor form that has functional properties. of or and The β1AR its was the β1AR T. S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) and and The was in of the to the the was by a green the and this an of the was the of the to The was of S. Salahpour A. E. S. D. M. Bouvier M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: Google Scholar). the of the are to as and respectively. of the which was a of Jr., D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), was of to β1AR an at the at this D.A. Green S.A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The was a by the and an The was with and in The was a protein a of the of the β1AR to The was and and the The was by with and the to the The was its and The was and by with and The a between the of the β2AR and the In some a of the was The was a HEK 293 cells in with bovine serum or or cells at a of and for the P. V. Y. T. Cell. Full Text PDF PubMed Scopus Google Scholar) or to the The cells in the for In some in HEK 293 cells expressing the β2AR cells co-expressing receptors and the in PBS, and with bovine serum for the cells with the in for an two in and two in PBS, cells and in for and at for at to of the receptor at with the addition of protein for of only protein was by at The with and in and and at to be used in the was the with bovine serum as a by to and to The was used for cells in PBS, with and in in at a of was at a of and a that the of the detected in the and with the The is by the of the by the the by the The by the detected the a the protein of the was to for the number of cells a with bovine serum as a determine the between each by increasing of the with a of cells as T.E. S. C. Bouvier M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Hebert T.E. J. 1998; Full Text PDF PubMed Scopus Google Scholar). cells with by with a in of and at for at to and cells. The was at for and the was in the used for adenylyl cyclase and and as number was a of as the of with for at in a of in the or of or to specific In some the of β1AR and β2AR a of the or or that of the subtypes but less of the receptor was with the as Biol. 2000; Google Scholar). with or and internalization was to to the β1AR, and was and in the of for at with or for and with to cells with for and for cells with for with a as for the receptor cyclase activity was in the to the of Y. C. M. PubMed Scopus Google Scholar) of protein in a of a in the of to or the at as of of with to adenylyl cyclase activity and by for and for the with the β-adrenergic or at in a and The for and the activity of the and MAPK was by with or at The and with the or to for the of a and in and stimulated for the with at and with and for at with PBS, the cells with a and serum for or in a of serum and BSA, with cells for at with PBS, was with the for in the by with cells with and was stimulated with a and with with a with was a with a in the of and a of indicating the of the with a the extracellular or with and to cells with or for at for with PBS, cells with with for cells with for and with with for and with for with BSA, with for and with The was to the for The was with of and was at as of to In a to determine whether the β2AR form a with the β1AR, a co-immunoprecipitation between β1AR and β2AR and GFP, was The ability of the β2AR to form or to heterodimerize with the β1AR was in HEK 293 cells co-expressing the with or or of the receptors a the of in the was a to and of the β2AR detected in both and cells. In no specific was detected at the or in the of cells co-expressing the receptor and the and the of the for the detected in the not that this receptor was and Taken together, as T.E. S. C. Bouvier M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. Salahpour A. E. S. D. M. Bouvier M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: Google Scholar, J. M. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), that the β2AR and β1AR can form and that and can between the two receptors as The detected in to that may dimers or such as that not by T.E. S. C. Bouvier M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The in this of the and the of to between the of we to as Although co-immunoprecipitation is a to the of for such as receptors is by that whether heterodimers be detected in was is a the of energy between a and a fluorescent that of in cells S. Salahpour A. E. S. D. M. Bouvier M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: Google Scholar, Y. Johnson Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). has been used to to for β2AR S. Salahpour A. E. S. D. M. Bouvier M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: Google Scholar), M. D. E. S. S. G. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and receptor K.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) In we have used a of the The of the of a as which a between and β2AR and β1AR homo- and the receptor to or in HEK 293 and the of energy between the two was the addition of C. of the the with a at that can GFP, in with a at but only if the two are the The is by the of the by the the by the the for the A was detected for both β1AR and β2AR homodimers, and a but significant was observed in cells expressing or indicating that heterodimers between the receptor subtypes form in cells. significant was detected or was co-expressed with at a similar as or the of the detected The between the observed for the homo- and heterodimers not a number of heterodimers, the of not strictly the number of dimers but the and between the energy and the that in the of the dimers for the significant detected in the the cells stimulated with not the functional consequences of heterodimerization by of several this cells with the β1AR, β2AR, or both receptors such that an number of receptors in each β2AR, β1AR β2AR, cells expressing the two receptor with the and of β1AR and In a of the ability of the β-adrenergic to the adenylyl cyclase was In the of receptor, a in that the of β2AR in HEK 293 cells of the β1AR, β2AR, or both receptors to similar in the adenylyl cyclase and stimulated and for β1AR and for β2AR and and for β1AR β2AR respectively. In the and stimulated and in the ability of or to adenylyl cyclase detected whether the receptors or not no significant in the or the of was we that the two receptor subtypes similar to with the adenylyl cyclase and that the formation of heterodimers no this signaling The of each receptor or to the and ERK1/2 was was by the β1AR, and this was not by co-expression with the β2AR In HEK 293 we not a of by the β2AR In a was observed between β1AR and β2AR in ability to phosphorylation of as by other of the β2AR in a activation of which at and to by A no in the phosphorylation of ERK1/2 be detected upon in cells expressing the β1AR did not ERK1/2 in the β1AR-expressing the ERK1/2 phosphorylation was in cells. in a similar to what was observed for the β1AR-expressing no ERK1/2 activity be detected in cells co-expressing both β1AR and β2AR both the β1AR and β1AR and β2AR together, no was of that the of ERK1/2 shown at was not to in the of receptor activation of the In we not in ERK1/2 activation of the two receptors not Given that the two receptors at suggest that heterodimerization the ERK1/2 several are in D. that of the β1AR by itself did not of β2AR in the we β1AR a expressing the by the for the β1AR the β2AR was between and in shown in a similar of ERK1/2 activity was upon co-expression of the two receptor subtypes. no was the co-expressed at of the data are in of ERK1/2 phosphorylation by β2AR in and of ERK1/2 activation is shown in the of each by in to by for various of HEK 293 cells with β2AR in the and of of both receptors was by and of for β1AR between and our of was each was by with are shown and at data a and and are as for β2AR and significant between and Given the internalization for the two the consequences of heterodimerization the internalization of each receptor both receptors are found at the a and of the β2AR expressing cells with to a internalization by the of receptor the that be detected as as β1AR-expressing the no the of the receptor at the significant internalization of the β1AR was detected a with the studies that that the β1AR is to agonist-promoted internalization T. 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In cells co-expressing the two receptor to significant internalization of the β1AR or the β2AR and indicating that of the β1AR the internalization of the in cells with both β1AR and both receptors are at the where they for the β2AR, internalization was observed in cells only or expressing and In no such internalization of was observed in cells co-expressing significant of the β1AR and The in some of cells co-expressing both internalization of β2AR of β1AR and in HEK 293 cells in to stimulation. and cells expressing and β1AR and for various with of and with with in are and the A is shown for cells which of both and cells and with in cells expressing both receptors at the cells expressing only or β2AR show receptor internalization the of β2AR internalized in the and of the β1AR, we two of the β2AR in the or of the we that of β2AR in the of to the β2AR at the of In the of the β1AR, the of β2AR that at the of was our in the of receptors as with not we of β2AR an in the of the β1AR, the of β2AR internalized is When the β2AR is alone, of receptors at the of in with the β1AR is present Taken together, that β2AR trafficking is in the of the have demonstrated in addition to forming homodimers, β1AR and β2AR can form heterodimers co-expressed in HEK 293 cells. shown both by co-immunoprecipitation and in cells. co-immunoprecipitation that the was at the an of the of as by to or not that receptors forming have demonstrated that co-expression of the two receptors to functional in the that the β1AR and β2AR as a to a with functional properties. is by the of ERK1/2 MAPK by the two receptors Given that the β1AR, alone, was of our suggest that the heterodimers a of the studies have demonstrated that the β1AR is less β2AR in ERK1/2 MAPK A. T. S. 2000; PubMed Scopus Google Scholar, A. E. S.A. B.A. 2000; PubMed Scopus Google Scholar). our this is the indicating that cells co-expressing the two receptors may have ERK1/2 responses to β-adrenergic stimulation. the β1AR and β2AR are in the and more both receptors are co-expressed in potential of this of the ERK1/2 receptor heterodimerization may itself in the of signaling by β-adrenergic stimulation. recent reports have demonstrated that to the stimulated by the β2AR, is an important of in C. S. A. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, S. D. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). In β2AR to in an of have demonstrated that this β2AR is of β2AR and in be by activation of β1AR, and this was by the of the studies S. D. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). is that this of may in has been demonstrated that of ERK1/2 may play a role in the of Y. T. S. H. T. Y. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). of a may be important the of β1AR and the of β2AR the A. T. S. 2000; PubMed Scopus Google Scholar, C. K. 1998; PubMed Scopus Google Scholar). may be important the to the β1AR is and increasing the of signaling specific to the of and the functional of heterodimerization. of β2AR to an of β1AR which is β2AR such as H. W. B. H. Koch W.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). responses to in with of the β1AR, β2AR number and similar to Jr., D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). C. M. T. E. E. G. and in Taken together, data are with the that each receptor in some the other for The that β1AR and β2AR similar to adenylyl cyclase of whether or not heterodimerization this pathway. studies that the β1AR a to adenylyl cyclase with the β2AR G. Bouvier M. Pharmacol. Google Scholar, S.A. Pharmacol. Google Scholar, L. Proc. Natl. Acad. Sci. U. S. 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Nature. 2002; 416: 199-202Crossref PubMed Scopus (1154) Google Scholar, G. Hoon M.A. Chandrashekar J. Zhang Y. Ryba N.J. Zuker C.S. Cell. 2001; 106: 381-390Abstract Full Text Full Text PDF PubMed Scopus (1392) Google Scholar). of between signaling is by the that and receptor signaling S. H. U. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). in have been to the formation of co-expression of and receptors T. R. V. G. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) or of and receptors M. E. R. A. A. N. P. R. R. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) to not receptor was In our that subtypes can form heterodimers with functional properties. Given the of β1AR and β2AR, be to the of heterodimerization in the and signaling of each receptor in In of the increasing number of reports of between receptor subtypes that oligomerization may a regulatory and Ethier for for with and for the

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