Subtype-specific Assembly of α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor Subunits Is Mediated by Their N-terminal Domains

Glutamate receptors (GluR) are oligomeric protein complexes formed by the assembly of four or perhaps five subunits. The rules that govern the selectivity of this process are not well understood. Here, we expressed combinations of subunits from two related GluR subfamilies in COS7 cells, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors. By co-immunoprecipitation experiments, we assessed the ability of AMPA receptor subunits to assemble into multimeric complexes. Subunits GluR1–4 associated with indistinguishable efficiency with each other, whereas the kainate receptor subunits GluR6 and 7 showed a much lower degree of association with GluR1. Using chimeric receptors and truncation fragments of subunits, we show that this assembly specificity is determined by N-terminal regions of these subunits and that the most N-terminal domain of GluR2 together with a membrane anchor efficiently associates with GluR1. Glutamate receptors (GluR) are oligomeric protein complexes formed by the assembly of four or perhaps five subunits. The rules that govern the selectivity of this process are not well understood. Here, we expressed combinations of subunits from two related GluR subfamilies in COS7 cells, the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate receptors. By co-immunoprecipitation experiments, we assessed the ability of AMPA receptor subunits to assemble into multimeric complexes. Subunits GluR1–4 associated with indistinguishable efficiency with each other, whereas the kainate receptor subunits GluR6 and 7 showed a much lower degree of association with GluR1. Using chimeric receptors and truncation fragments of subunits, we show that this assembly specificity is determined by N-terminal regions of these subunits and that the most N-terminal domain of GluR2 together with a membrane anchor efficiently associates with GluR1. Fast excitatory synaptic transmission in the mammalian central nervous system is primarily mediated by multimeric ligand-gated ion channels, which are activated by the neurotransmitter glutamate. Based on pharmacological properties and sequence similarities, these receptors fall into three main classes: the glutamate receptor (GluR) 1The abbreviations used are: GluR, glutamate receptor; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; TMD, transmembrane domain; MuSK, muscle-specific kinase; PAGE, polyacrylamide gel electrophoresis; mAb, monoclonal antibody; pAb, polyclonal antibody; PCR, polymerase chain reaction; PBS, phosphate-buffered saline; SB, solubilization buffer subunits 1–4 form the family of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, subunits GluR5–7 and KA1 and KA2 are the family of kainate receptors, and subunits NR1 and NR2A–D are components ofN-methyl-d-aspartate receptors (1Hollmann M. Heinemann S. Annu. Rev. Neurosci. 1994; 17: 31-108Crossref PubMed Scopus (3668) Google Scholar, 2Michaelis E.K. Prog. Neurobiol. 1998; 54: 369-415Crossref PubMed Scopus (482) Google Scholar). Functional receptors of each type are composed of multiple subunits. Recent experiments suggest that each receptor complex contains four subunits (3Laube B. Kuhse J. Betz H. J. Neurosci. 1998; 18: 2954-2961Crossref PubMed Google Scholar, 4Mano I. Teichberg V.I. Neuroreports. 1998; 9: 327-331Crossref PubMed Scopus (103) Google Scholar, 5Rosenmund C. Stern-Bach Y. Stevens C.F. Science. 1998; 280: 1596-1599Crossref PubMed Scopus (654) Google Scholar, 6Wu T.-Y. Liu C.-I. Chang Y.-C. Biochem. J. 1996; 319: 731-739Crossref PubMed Scopus (30) Google Scholar), whereas previously a pentameric structure has been favored (7Wenthold R.J. Yokotani N. Doi K. Wada K. J. Biol. Chem. 1992; 267: 501-507Abstract Full Text PDF PubMed Google Scholar, 8Ferrier-Montiel A.V. Montal M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 27412744Google Scholar, 9Premkumar L.S. Auerbach A. J. Gen. Physiol. 1997; 110: 485-502Crossref PubMed Scopus (101) Google Scholar). Recombinant expression of an individual type of subunit in nonneuronal cells in many cases leads to the formation of functional homomeric ion channels. Coexpression of two or more subunits of the same class, however, mainly directs the formation of heteromeric channels (10Verdoorn T.A. Burnashev N. Monyer H. Seeburg P.H. Sakmann B. Science. 1991; 252: 1715-1718Crossref PubMed Scopus (679) Google Scholar, 11Boulter J. Hollmann M. O'Shea-Greenfield H.M. Deneris E. Maron C. Heinemann S. Science. 1990; 249: 1033-1037Crossref PubMed Scopus (742) Google Scholar, 12Hollmann M. O'Shea-Greenfield A. Rogers S.W. Heinemann S. Nature. 1989; 342: 643-648Crossref PubMed Scopus (782) Google Scholar, 13Keinänen K. Wisden W. Sommer B. Werner P. Herb A. Verdoorn T.A. Sakmann B. Seeburg P.H. Science. 1990; 249: 556-560Crossref PubMed Scopus (1199) Google Scholar). Their electrophysiological characteristics are different from those of their homomeric counterparts and often are quite similar to channels present in neurons. In vivo, GluRs are thought to be predominantly or perhaps exclusively composed of heteromeric channels, based on their functional similarity with recombinant channels as well as co-immunoprecipitation experiments (7Wenthold R.J. Yokotani N. Doi K. Wada K. J. Biol. Chem. 1992; 267: 501-507Abstract Full Text PDF PubMed Google Scholar,14Brose N. Huntley G.W. Stern-Bach Y. Sharma G. Morrison J.H. Heinemann S.F. J. Biol. Chem. 1994; 269: 16780-16784Abstract Full Text PDF PubMed Google Scholar, 15Puchalski R.B. Louis J.-C. Brose N. Traynelis S.F. Egebjerg J. Kukekov V. Wenthold R.J. Rogers S.W. Lin F. Moran T. Morrison J.H. Heinemann S.F. Neuron. 1994; 13: 131-147Abstract Full Text PDF PubMed Scopus (143) Google Scholar, 16Wenthold R.J. Petralia R.S. Blahos II, J.B. Niedzielski A.S. J. Neurosci. 1996; 16: 1982-1989Crossref PubMed Google Scholar). The subunit composition of GluRs determines the electrophysiological characteristics of these ligand-gated ion channels. For example, AMPA receptors lacking the GluR2 subunit are permeable for calcium, whereas channels containing at least one GluR2 subunit not into the cells (10Verdoorn T.A. Burnashev N. Monyer H. Seeburg P.H. Sakmann B. Science. 1991; 252: 1715-1718Crossref PubMed Scopus (679) Google Scholar, M. M. Heinemann S. Science. 1991; 252: PubMed Scopus Google Scholar). of that many subunits from different subfamilies of GluRs R.B. Louis J.-C. Brose N. Traynelis S.F. Egebjerg J. Kukekov V. Wenthold R.J. Rogers S.W. Lin F. Moran T. Morrison J.H. Heinemann S.F. Neuron. 1994; 13: 131-147Abstract Full Text PDF PubMed Scopus (143) Google Scholar, B. E. S. J. J. Neurosci. 1997; 17: PubMed Google Scholar, B. E. P. F. J. Neuron. 1992; 9: Full Text PDF PubMed Scopus Google Scholar, Y. N. Y. K. Y. J. Neurosci. 1997; 17: PubMed Google Scholar). is by of most subunits N. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar, B. K. Verdoorn T.A. Wisden W. Burnashev N. Herb A. M. T. Sakmann B. Seeburg P.H. Science. 1990; 249: PubMed Scopus Google Scholar). The rules the assembly of GluRs from individual subunits are not is that association and the composition of the GluRs in each is determined by the of individual subunits. is that subunits with one or a of subunits and the formation of GluRs with a subunit for a receptor assembly is the of individual subunits of this neurotransmitter receptor association of subunits in an process P. Neuron. Full Text PDF PubMed Scopus Google Scholar, Y. S. J. Biol. 1991; PubMed Scopus Google Scholar, T. Full Text PDF PubMed Scopus Google Scholar, S.F. J. Biol. 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Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, S. P. G. B. C. S. R.J. Neuron. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. Neuron. Full Text Full Text PDF PubMed Scopus Google Scholar). has been to to the N-terminal a domain to the protein M. W. F. Neuron. 1992; Full Text PDF PubMed Scopus Google Scholar). Here, we the of which of AMPA receptor subunits their assembly into receptor complexes. expressed different of subunits in COS7 cells and subunit association by AMPA receptor subunits not kainate receptor subunits associated with the subunit with Using chimeric receptors and truncation fragments of subunits, we show that this specificity of assembly is determined by N-terminal regions of subunits. from from from and from from from The GluR2 and from and P. Seeburg the of the AMPA receptor subunit and the kainate receptor subunit GluR6 as well as the and GluR6 and used for the of the from M. Hollmann The from the H. 1994; PubMed Scopus Google by and and into the W. Neuron. Full Text PDF PubMed Scopus Google and The of the S. H. H. J. Biol. Chem. 1989; Full Text PDF PubMed Google by a the S.F. 1996; PubMed Scopus Google with and the containing the into of By with and the in a with two The and the and the the the that to be at their by an the an or a into and and into and for and with a into the and into and and in the of the AMPA subunit the of by a The sequence into the with and and into the C. W. J. Biochem. 1998; PubMed Scopus Google into and at the sequence K. Wisden W. Sommer B. Werner P. Herb A. Verdoorn T.A. Sakmann B. Seeburg P.H. Science. 1990; 249: 556-560Crossref PubMed Scopus (1199) Google Scholar). The of the and acid of the fragments are to K. Wisden W. Sommer B. Werner P. Herb A. Verdoorn T.A. Sakmann B. Seeburg P.H. Science. 1990; 249: 556-560Crossref PubMed Scopus (1199) Google and and and and and C. Hollmann M. J. Neurosci. 1997; 17: PubMed Google with and and the containing the of GluR6 at the of The and into the 13Keinänen K. Wisden W. Sommer B. Werner P. Herb A. Verdoorn T.A. Sakmann B. Seeburg P.H. Science. 1990; 249: 556-560Crossref PubMed Scopus (1199) Google Scholar). and by or and The of the with or the into these with the with the of polymerase and with and of GluR6 the chimeric in the expression and by or The of the with or the into with and into the the that been with the same and as well as the containing the transmembrane domain of GluR2 by The and and and into into by the of for and The for and from into and C. two and two the transmembrane domain of GluR2 containing a at the and at the as well as to the of A. of each used for into from into containing the transmembrane domain The of the by expression in COS7 cells, and regions with the or the transmembrane to the of 13Keinänen K. Wisden W. Sommer B. Werner P. Herb A. Verdoorn T.A. Sakmann B. Seeburg P.H. Science. 1990; 249: 556-560Crossref PubMed Scopus (1199) Google by and and into the and The protein containing an N-terminal in and as C. W. J. Biochem. 1998; PubMed Scopus Google Scholar). with the protein in the the an with the protein to a of and to COS7 cells at a of in in COS7 cells as previously C. H. Biol. PubMed Scopus Google with that to the of and the to cells on the in phosphate-buffered containing and COS7 cells with of solubilization buffer in phosphate-buffered containing for at in a the at for at and the protein of the determined acid with as In the solubilization experiments in from of the and together with a of the by and and of subunits, and fragments of cells with for the GluR subunits, or the chimeric and For the of cells for with a from the and by and is the of in the from two For the of cells with the not of not be is in an of the fragments and which not a transmembrane most or to the and by fragments in the in a COS7 cells with for the GluR subunits, or the chimeric and For the of cells for with a from the and by and is the of in the from two For the of cells with the not of not be is in an of the fragments and which not a transmembrane most or to the and by fragments in the of with of in for at in a three with SB, the with in The three in of containing at by three with SB, the with in for by three with in and for at The three with and with buffer of buffer containing and and for at The by and the of the at The of protein with to the of the same protein present in the The for the of or the or by the in For the association efficiency expressed as of the association for the of and GluR2 of with in solubilization buffer at to of oligomeric The from by the three with buffer The with in SB, with of and The three with SB, and the by the with of buffer for at The two and the of protein as well as present in the determined by from Biochem. PubMed Scopus Google and by Nature. PubMed Scopus Google Scholar). to J. J. Biochem. PubMed Scopus Google the buffer system by C. W. H. F. J. Biochem. PubMed Scopus Google Scholar), with the as in the and the by as a as W. Betz W. J. 1989; PubMed Scopus Google with of on a membrane The membrane with the or the and to the membrane and with of buffer containing and for The by of and the at COS7 cells with for the to the and for at three with phosphate-buffered containing and the cells for with buffer and in The cells for to in buffer and with to the assembly of AMPA and receptor subunits into heteromeric receptors by and subunits in COS7 cells and heteromeric receptors with a this we the into expression for in COS7 the four AMPA receptor subunits two kainate receptor subunits and and a membrane protein of the muscle-specific subunits expressed or of a from the to the of the or to the a sequence and to expressed receptor with a we from the of multiple with different of into COS7 cells of the as on with the For of homomeric and heteromeric we an the AMPA receptor subunit GluR1. The a protein that of an N-terminal by the sequence of GluR1. of the subunit is and the most different GluR subunits. from this a of the in COS7 cells that been with expression and subunits. with of the three AMPA receptor the kainate receptor subunits GluR6 and 7 or the protein MuSK, The to more of subunit from of COS7 cells, as determined by and not In to the of subunit on heteromeric receptor we expressed a of GluR2 subunit with of containing at least one subunit and the of GluR2 subunits present in heteromeric complexes by a In the of a of subunits, of GluR2 subunits by the and been into heteromeric complexes a of expression of the a present in the of GluR2 subunit in heteromeric receptors with lower In of the experiments, the the of the of receptor complexes present in cells, we containing or and by In two at and the subunits, the or complexes. and W. of not assemble into homomeric or heteromeric complexes. we the individual GluR subunits in their ability to with the The AMPA receptor subunits and the kainate receptor subunits GluR6 and as well as the as protein each into COS7 cells together with the The of heteromeric assembly by of the AMPA receptor subunits with the subunit with efficiency for a of the subunit for assembly with one of the AMPA receptor subunits. In the kainate receptor subunits GluR6 and 7 of this of subunits a to assemble with AMPA receptor subunits as with the protein protein of the association with which as assembly in of the The of protein association a the of cells or GluR subunit or at most of the of AMPA receptor subunits GluR2 in from cells GluR2 not GluR1. experiments in to co-immunoprecipitation experiments with with similar not of on the association of subunits in we expressed GluR2 with a to the or to the with similar that the not with receptor assembly of a different N-terminal to has on functional properties and synaptic of this subunit M. S. M. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). In co-immunoprecipitation experiments, AMPA receptor subunits with each into heteromeric receptors. which regions of the GluRs for we a of chimeric receptor subunits of of the AMPA receptor subunit to regions of the kainate receptor subunit containing the for the with GluR2 or GluR6 subunits, and their ability to assemble with one of these subunits determined by co-immunoprecipitation The chimeric subunit which contains the of with GluR2 with an efficiency similar to that for the subunit the N-terminal domain and the transmembrane of with the of GluR6 the association with chimeric receptors containing the N-terminal of GluR6 efficiently GluR6 subunits whereas the N-terminal of not efficiently with this The containing GluR6 sequence not be assessed by the same type of co-immunoprecipitation not the for the used for assembly of these we the the sequence and the of the chimeric receptors these with into COS7 cells and the expressed the containing N-terminal sequence with or the and GluR6 sequence with the subunit with an efficiency indistinguishable from that of GluR2 these show that the regions for the assembly of GluRs in the N-terminal of their subunits. In to regions in AMPA receptor subunits receptor we expressed different fragments of the GluR2 subunit together with the subunit and their degree of a of truncation fragments of from the fragments be on as at from their In an at much which most multimeric of the in association with the subunit indistinguishable from the association of the GluR2 subunit of the transmembrane and as in and of the thought to be of the ion as in the association with GluR1. that in with the with the chimeric receptors the of the receptor is not for In of the most N-terminal domain as in association with GluR to a the for kainate receptor subunits. of the transmembrane domain in which not with GluR1. In which at a the in the formation of the glutamate an for the transmembrane in subunit assembly of AMPA receptors the assembly of GluR2 fragments with GluR1. domain sequence association with transmembrane the of a transmembrane be to the N-terminal fragments to the membrane in an for In this the sequence of this domain not be to be of for these we the transmembrane domain of by transmembrane domain the domain and assessed the of the transmembrane protein to assemble with with with the same efficiency as or the GluR2 subunit that the is the of a transmembrane of sequence to be for subunit by experiments, which showed that transmembrane domain expressed in the of sequence not the of the protein similar of association for a the transmembrane and and the to the assembly of the most N-terminal domain in the of a transmembrane transmembrane domain or to this and the fragments and together with into COS7 fragments the by with the subunit with efficiency as with the GluR2 subunit that the most domain subunit assembly is in the more N-terminal of the which is not of the glutamate The lower of fragments and in with the subunit suggest that of the N-terminal domain in subunit the assembly be to of these by of of often their and in the by the system C. A. Biol. PubMed Scopus Google Scholar). an of much by these we which of each be in a buffer and which expressed on the more of the subunits and the chimeric in the of fragments be to a similar or fragments and which not transmembrane as well as these fragments to transmembrane to a degree in the The of these fragments be by the of one of the glutamate which is formed by an association of and M. K. J. 1998; 17: PubMed Scopus Google Scholar, A. B. Betz H. Kuhse J. Neuron. 1994; Full Text PDF PubMed Scopus Google Scholar, Y. B. M. Heinemann S.F. 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In this we this to regions that association of AMPA receptor subunits. expression in COS7 cells, the subunit each of the AMPA receptor subunits or with indistinguishable In a kainate receptor subunit to a much lower however, the of the specificity of GluR assembly in COS7 cells, an from functional of expressed experiments from of show a similar of subunits subfamilies N. Huntley G.W. Stern-Bach Y. Sharma G. Morrison J.H. Heinemann S.F. J. Biol. Chem. 1994; 269: 16780-16784Abstract Full Text PDF PubMed Google Scholar, 15Puchalski R.B. Louis J.-C. Brose N. Traynelis S.F. Egebjerg J. Kukekov V. Wenthold R.J. Rogers S.W. Lin F. Moran T. Morrison J.H. Heinemann S.F. Neuron. 1994; 13: 131-147Abstract Full Text PDF PubMed Scopus (143) Google Scholar, 16Wenthold R.J. Petralia R.S. Blahos II, J.B. Niedzielski A.S. J. Neurosci. 1996; 16: 1982-1989Crossref PubMed Google Scholar, R.J. Petralia R.S. J. Biol. 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Science. 1991; 252: 1715-1718Crossref PubMed Scopus (679) Google Scholar, 11Boulter J. Hollmann M. O'Shea-Greenfield H.M. Deneris E. Maron C. Heinemann S. Science. 1990; 249: 1033-1037Crossref PubMed Scopus (742) Google Scholar). has been to the efficiency of subunit assembly in these functional the expression of individual subunits are not In the of ion channels with and ion to be in by in which we expression and not on functional properties for of receptor complexes. that AMPA receptor subunits not a assembly of subunit similar association of related subunits for different of the which for each J. B. Betz H. Neuron. Full Text PDF PubMed Scopus Google Scholar). 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The specificity of of the chimeric receptors is by the that the of the N-terminal of subunit with the of GluR6 on the assembly with AMPA and kainate this the with whereas the with GluR2 to the with kainate receptor subunits. an association not be by of the chimeric the association with GluR2 and association with GluR6 to be to the or of regions subunit these for the assembly of kainate receptors, N-terminal of the subunits are as this not The specificity of association is more to for of fragments with be assembly or of of fragments by in and expression fragments suggest that the of we based mainly on fragments the of association with at a to that of the of fragments to this we the of fragments in the of which for fragments expression in mammalian cells, of homomeric or heteromeric AMPA receptors are on the A. P.H. 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