{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:37:59Z","timestamp":1787841479453,"version":"build-2784847793"},"reference-count":118,"publisher":"Rockefeller University Press","issue":"6","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["803714"],"award-info":[{"award-number":["803714"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000691","name":"Academy of Medical Sciences Springboard Award","doi-asserted-by":"publisher","award":["SBF007\\100104"],"award-info":[{"award-number":["SBF007\\100104"]}],"id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011693","name":"Department for Business, Energy and Industrial Strategy, UK Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011693","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000361","name":"Diabetes UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"UKRI Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/T00875X\/1"],"award-info":[{"award-number":["BB\/T00875X\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"Horizon 2020","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,11,2]]},"abstract":"<jats:p>Most ionotropic neurotransmitter receptors are hetero-oligomers of three to five homologous subunits assembled into membrane-spanning ion channels. Mammalian AMPA-type glutamate receptors (AMPARs), which emerged in animals with centralized nervous systems and now mediate most of the excitatory synaptic signaling in our brain, readily assemble as homotetramers, yet often occur as heterotetramers of two to three different AMPAR subunits. Here, we looked for unifying functional properties of the AMPAR family using molecular phylogenetics, together with electrophysiological and pharmacological characterization of heterologously expressed AMPARs from the three major lineages within bilaterian animals. Our results suggest that the hallmark of AMPAR evolution is selective activation by glutamate, fast kinetics, and the duplication of AMPAR genes independently in new animal lineages, such that most major bilaterian groups have relatively unique complements of AMPAR genes. Moreover, in diverse bilaterians, these novel AMPAR subunits have (1) come to rely on each other for functional expression, resulting in obligate heterotetrameric AMPARs, and (2) sub-functionalized, with various subunits contributing differently to channel activation or ion permeation. Remarkably, this evolution appears to have independently converged on a complement of calcium-sensitive and calcium-insensitive AMPARs in mammals and worms via biophysically similar but genetically different mechanisms.<\/jats:p>","DOI":"10.1085\/jgp.202614039","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T06:20:31Z","timestamp":1785910831000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Tunable AMPA receptor function via recurrent evolution of heterotetramers"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7260-1472","authenticated-orcid":true,"given":"Yuhong","family":"Wang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zga2b32","id-type":"ROR","asserted-by":"publisher"}],"name":"Michael Sars Centre, University of Bergen 1 , Bergen,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9420-0916","authenticated-orcid":true,"given":"Alexander","family":"Edwards","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01nrxwf90","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biological Sciences, University of Edinburgh 2 , Edinburgh,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2310-960X","authenticated-orcid":true,"given":"Jelena","family":"Baranovic","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01nrxwf90","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biological Sciences, University of Edinburgh 2 , Edinburgh,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4888-4098","authenticated-orcid":true,"given":"Timothy","family":"Lynagh","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03zga2b32","id-type":"ROR","asserted-by":"publisher"}],"name":"Michael Sars Centre, University of Bergen 1 , Bergen,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"2026082709571565100_bib1","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.str.2023.03.013","article-title":"Desensitization dynamics of the AMPA receptor","volume":"31","author":"Aittoniemi","year":"2023","journal-title":"Structure"},{"key":"2026082709571565100_bib2","doi-asserted-by":"publisher","first-page":"E6048","DOI":"10.1073\/pnas.1513771112","article-title":"Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes","volume":"112","author":"Alberstein","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib3","doi-asserted-by":"publisher","first-page":"2617","DOI":"10.1523\/jneurosci.2667-15.2016","article-title":"A molecular determinant of subtype-specific desensitization in ionotropic glutamate receptors","volume":"36","author":"Alsaloum","year":"2016","journal-title":"J. Neurosci."},{"key":"2026082709571565100_bib4","doi-asserted-by":"publisher","first-page":"3389","DOI":"10.1093\/nar\/25.17.3389","article-title":"Gapped BLAST and PSI-BLAST: A new generation of protein database search programs","volume":"25","author":"Altschul","year":"1997","journal-title":"Nucleic Acids Res."},{"key":"2026082709571565100_bib5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000408","article-title":"Active mode of excretion across digestive tissues predates the origin of excretory organs","volume":"17","author":"Andrikou","year":"2019","journal-title":"PLoS Biol."},{"key":"2026082709571565100_bib6","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/s0896-6273(00)00094-5","article-title":"Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: Crystal structures of the GluR2 ligand binding core","volume":"28","author":"Armstrong","year":"2000","journal-title":"Neuron"},{"key":"2026082709571565100_bib7","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1146\/annurev-physiol-020911-153236","article-title":"The Calyx of held synapse: From model synapse to auditory relay","volume":"74","author":"Borst","year":"2012","journal-title":"Annu. Rev. Physiol."},{"key":"2026082709571565100_bib8","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.tins.2016.11.005","article-title":"Back to the basics: Cnidarians start to fire","volume":"40","author":"Bosch","year":"2017","journal-title":"Trends Neurosci."},{"key":"2026082709571565100_bib9","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.tins.2023.05.002","article-title":"Excitatory GluN1\/GluN3A glycine receptors (eGlyRs) in brain signaling","volume":"46","author":"Bossi","year":"2023","journal-title":"Trends Neurosci."},{"key":"2026082709571565100_bib10","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.tins.2026.01.006","article-title":"Splicing, RNA editing, and auxiliary subunits shaped AMPA receptor function through coordinated evolution","volume":"49","author":"Bowie","year":"2026","journal-title":"Trends Neurosci."},{"key":"2026082709571565100_bib11","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1111\/imb.12791","article-title":"Different efficiency of auxiliary\/chaperone proteins to promote the functional reconstitution of honeybee glutamate and acetylcholine receptors in Xenopus laevis oocytes","volume":"31","author":"Brunello","year":"2022","journal-title":"Insect Mol. Biol."},{"key":"2026082709571565100_bib12","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nature16520","article-title":"Xenacoelomorpha is the sister group to Nephrozoa","volume":"530","author":"Cannon","year":"2016","journal-title":"Nature"},{"key":"2026082709571565100_bib13","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1016\/j.neuron.2012.04.020","article-title":"Coupled control of desensitization and gating by the ligand binding domain of glutamate receptors","volume":"74","author":"Carbone","year":"2012","journal-title":"Neuron"},{"key":"2026082709571565100_bib14","doi-asserted-by":"publisher","first-page":"10178","DOI":"10.1038\/ncomms10178","article-title":"Superactivation of AMPA receptors by auxiliary proteins","volume":"7","author":"Carbone","year":"2016","journal-title":"Nat. Commun."},{"key":"2026082709571565100_bib15","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/s0169-328x(98)00086-2","article-title":"Molecular and electrophysiological characterizations of fGluR3\u03b1, an ionotropic glutamate receptor subunit of a teleost fish","volume":"57","author":"Chang","year":"1998","journal-title":"Mol. Brain Res."},{"key":"2026082709571565100_bib16","doi-asserted-by":"publisher","first-page":"1234","DOI":"10.1016\/j.cell.2017.07.045","article-title":"Activation and desensitization mechanism of AMPA receptor-TARP complex by cryo-EM","volume":"170","author":"Chen","year":"2017","journal-title":"Cell"},{"key":"2026082709571565100_bib17","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s00239-004-0291-5","article-title":"The mutually exclusive flip and flop exons of AMPA receptor genes were derived from an intragenic duplication in the vertebrate lineage","volume":"62","author":"Chen","year":"2006","journal-title":"J. Mol. Evol."},{"key":"2026082709571565100_bib18","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaz3154","article-title":"The NALCN channel complex is voltage sensitive and directly modulated by extracellular calcium","volume":"6","author":"Chua","year":"2020","journal-title":"Sci. Adv."},{"key":"2026082709571565100_bib19","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/s44320-024-00030-z","article-title":"Mutational biases favor complexity increases in protein interaction networks after gene duplication","volume":"20","author":"Cisneros","year":"2024","journal-title":"Mol. Syst. Biol."},{"key":"2026082709571565100_bib20","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1126\/science.1359647","article-title":"The time course of glutamate in the synaptic cleft","volume":"258","author":"Clements","year":"1992","journal-title":"Science"},{"key":"2026082709571565100_bib21","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41583-025-00983-6","article-title":"The evolutionary origins of synaptic proteins and their changing roles in different organisms across evolution","volume":"27","author":"Colgren","year":"2025","journal-title":"Nat. Rev. Neurosci."},{"key":"2026082709571565100_bib22","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1038\/nrg2482","article-title":"Turning a hobby into a job: How duplicated genes find new functions","volume":"9","author":"Conant","year":"2008","journal-title":"Nat. Rev. Genet."},{"key":"2026082709571565100_bib23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2414756122","article-title":"Symmetry facilitated the evolution of heterospecificity and high-order stoichiometry in vertebrate hemoglobin","volume":"122","author":"Cortez-Romero","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib24","doi-asserted-by":"publisher","first-page":"2655","DOI":"10.1113\/JP279029","article-title":"Ca2+-permeable AMPA receptors and their auxiliary subunits in synaptic plasticity and disease","volume":"599","author":"Cull-Candy","year":"2021","journal-title":"J. Physiol."},{"key":"2026082709571565100_bib25","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1002\/cne.21670","article-title":"Visualizing glutamatergic cell bodies and synapses in Drosophila larval and adult CNS","volume":"508","author":"Daniels","year":"2008","journal-title":"J. Comp. Neurol."},{"key":"2026082709571565100_bib26","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1016\/j.neuron.2016.01.038","article-title":"Distinct structural pathways coordinate the activation of AMPA receptor-auxiliary subunit complexes","volume":"89","author":"Dawe","year":"2016","journal-title":"Neuron"},{"key":"2026082709571565100_bib27","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1016\/j.neuron.2019.01.045","article-title":"Chemoconnectomics: Mapping chemical transmission in Drosophila","volume":"101","author":"Deng","year":"2019","journal-title":"Neuron"},{"key":"2026082709571565100_bib28","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/j.neuron.2018.10.018","article-title":"The AMPA receptor code of synaptic plasticity","volume":"100","author":"Diering","year":"2018","journal-title":"Neuron"},{"key":"2026082709571565100_bib29","doi-asserted-by":"publisher","first-page":"12126","DOI":"10.1038\/s41598-022-15526-7","article-title":"iCodon customizes gene expression based on the codon composition","volume":"12","author":"Diez","year":"2022","journal-title":"Sci. Rep."},{"key":"2026082709571565100_bib30","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1126\/science.aai7685","article-title":"Gene duplication can impart fragility, not robustness, in the yeast protein interaction network","volume":"355","author":"Diss","year":"2017","journal-title":"Science"},{"key":"2026082709571565100_bib31","doi-asserted-by":"publisher","first-page":"8961","DOI":"10.1073\/pnas.1407018111","article-title":"Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala","volume":"111","author":"Du","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0004826","article-title":"Recent duplication and functional divergence in parasitic nematode levamisole-sensitive acetylcholine receptors","volume":"10","author":"Duguet","year":"2016","journal-title":"PLoS Negl. Trop. Dis."},{"key":"2026082709571565100_bib33","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/s41586-025-09289-0","article-title":"Gating and noelin clustering of native Ca2+-permeable AMPA receptors","volume":"645","author":"Fang","year":"2025","journal-title":"Nature"},{"key":"2026082709571565100_bib34","doi-asserted-by":"publisher","first-page":"1662316","DOI":"10.3389\/fphar.2025.1662316","article-title":"Structure and gating of kainate receptors","volume":"16","author":"Gangwar","year":"2025","journal-title":"Front. Pharmacol."},{"key":"2026082709571565100_bib35","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1038\/s41594-023-01080-x","article-title":"Modulation of GluA2\u2013\u03b35 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2","volume":"30","author":"Gangwar","year":"2023","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026082709571565100_bib36","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau6173","article-title":"Acoel genome reveals the regulatory landscape of whole-body regeneration","volume":"363","author":"Gehrke","year":"2019","journal-title":"Science"},{"key":"2026082709571565100_bib37","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/0896-6273(95)90076-4","article-title":"Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS","volume":"15","author":"Geiger","year":"1995","journal-title":"Neuron"},{"key":"2026082709571565100_bib38","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1093\/sysbio\/syq010","article-title":"New algorithms and methods to estimate maximum-likelihood phylogenies: Assessing the performance of PhyML 3.0","volume":"59","author":"Guindon","year":"2010","journal-title":"Syst. Biol."},{"key":"2026082709571565100_bib39","doi-asserted-by":"publisher","first-page":"R141","DOI":"10.1186\/gb-2007-8-7-r141","article-title":"Bias in phylogenetic tree reconciliation methods: Implications for vertebrate genome evolution","volume":"8","author":"Hahn","year":"2007","journal-title":"Genome Biol."},{"key":"2026082709571565100_bib40","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1124\/pharmrev.120.000131","article-title":"Structure, function, and pharmacology of glutamate receptor ion channels","volume":"73","author":"Hansen","year":"2021","journal-title":"Pharmacol. Rev"},{"key":"2026082709571565100_bib41","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.45530","article-title":"The genetic factors of bilaterian evolution","volume":"9","author":"Heger","year":"2020","journal-title":"Elife"},{"key":"2026082709571565100_bib42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2425172122","article-title":"Atomistic mechanisms of calcium permeation modulated by Q\/R editing and selectivity filter mutations in GluA2 AMPA receptors","volume":"122","author":"Heiser","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib43","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav9011","article-title":"Architecture of the heteromeric GluA1\/2 AMPA receptor in complex with the auxiliary subunit TARP \u03b38","volume":"364","author":"Herguedas","year":"2019","journal-title":"Science"},{"key":"2026082709571565100_bib44","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/0896-6273(90)90162-9","article-title":"Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices","volume":"5","author":"Hestrin","year":"1990","journal-title":"Neuron"},{"key":"2026082709571565100_bib45","doi-asserted-by":"publisher","first-page":"3939","DOI":"10.1073\/pnas.1612943114","article-title":"AMPA glutamate receptors are required for sensory-organ formation and morphogenesis in the basal chordate","volume":"114","author":"Hirai","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib46","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1093\/molbev\/msx281","article-title":"UFBoot2: Improving the ultrafast bootstrap approximation","volume":"35","author":"Hoang","year":"2018","journal-title":"Mol. Biol. Evol."},{"key":"2026082709571565100_bib47","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1113\/jphysiol.1952.sp004764","article-title":"A quantitative description of membrane current and its application to conduction and excitation in nerve","volume":"117","author":"Hodgkin","year":"1952","journal-title":"J. Physiol."},{"key":"2026082709571565100_bib48","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1016\/j.neuron.2013.10.050","article-title":"Kinesin-1 regulates synaptic strength by mediating the delivery, removal, and redistribution of AMPA receptors","volume":"80","author":"Hoerndli","year":"2013","journal-title":"Neuron"},{"key":"2026082709571565100_bib49","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1126\/science.1709304","article-title":"Ca2+ permeability of KA-AMPA\u2014gated glutamate receptor channels depends on subunit composition","volume":"252","author":"Hollmann","year":"1991","journal-title":"Science"},{"key":"2026082709571565100_bib50","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/s12862-020-01720-6","article-title":"Ancestral morphology of Ecdysozoa constrained by an early Cambrian stem group ecdysozoan","volume":"20","author":"Howard","year":"2020","journal-title":"BMC Evol. Biol."},{"key":"2026082709571565100_bib51","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1007\/s10126-016-9720-x","article-title":"Genome-wide analysis of alternative splicing provides insights into stress adaptation of the pacific oyster","volume":"18","author":"Huang","year":"2016","journal-title":"Mar. Biotechnol."},{"key":"2026082709571565100_bib52","doi-asserted-by":"publisher","first-page":"2612","DOI":"10.1038\/s41467-023-38016-4","article-title":"Acoel single-cell atlas reveals expression dynamics and heterogeneity of adult pluripotent stem cells","volume":"14","author":"Hulett","year":"2023","journal-title":"Nat. Commun."},{"key":"2026082709571565100_bib53","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.neuron.2011.04.007","article-title":"The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits","volume":"70","author":"Jackson","year":"2011","journal-title":"Neuron"},{"key":"2026082709571565100_bib54","doi-asserted-by":"publisher","first-page":"15749","DOI":"10.1073\/pnas.1512296112","article-title":"AMPA receptor inhibition by synaptically released zinc","volume":"112","author":"Kalappa","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib55","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1093\/nar\/gkf436","article-title":"MAFFT: A novel method for rapid multiple sequence alignment based on fast Fourier transform","volume":"30","author":"Katoh","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"2026082709571565100_bib56","doi-asserted-by":"publisher","first-page":"556","DOI":"10.1126\/science.2166337","article-title":"A family of AMPA-selective glutamate receptors","volume":"249","author":"Kein\u00e4nen","year":"1990","journal-title":"Science"},{"key":"2026082709571565100_bib57","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1093\/nar\/gkl924","article-title":"Different levels of alternative splicing among eukaryotes","volume":"35","author":"Kim","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"2026082709571565100_bib58","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/s0014-5793(01)03183-0","article-title":"Q\/R RNA editing of the AMPA receptor subunit 2 (GRIA2) transcript evolves no later than the appearance of cartilaginous fishes","volume":"509","author":"Kung","year":"2001","journal-title":"FEBS Lett."},{"key":"2026082709571565100_bib59","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.neuron.2009.01.010","article-title":"Dscam mediates remodeling of glutamate receptors in Aplysia during de novo and learning-related synapse formation","volume":"61","author":"Li","year":"2009","journal-title":"Neuron"},{"key":"2026082709571565100_bib60","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/j.neuron.2016.10.058","article-title":"Novel functional properties of Drosophila CNS glutamate receptors","volume":"92","author":"Li","year":"2016","journal-title":"Neuron"},{"key":"2026082709571565100_bib61","doi-asserted-by":"publisher","first-page":"E846","DOI":"10.1073\/pnas.1501195112","article-title":"Convergence of ion channel genome content in early animal evolution","volume":"112","author":"Liebeskind","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib62","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002661","article-title":"Chromosome-level genome assemblies of 2 hemichordates provide new insights into deuterostome origin and chromosome evolution","volume":"22","author":"Lin","year":"2024","journal-title":"PLoS Biol."},{"key":"2026082709571565100_bib63","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3002794","article-title":"A taxon-rich and genome-scale phylogeny of Opisthokonta","volume":"22","author":"Liu","year":"2024","journal-title":"PLoS Biol."},{"key":"2026082709571565100_bib64","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.tins.2007.01.006","article-title":"Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death","volume":"30","author":"Liu","year":"2007","journal-title":"Trends Neurosci."},{"key":"2026082709571565100_bib65","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.neuron.2009.02.027","article-title":"Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach","volume":"62","author":"Lu","year":"2009","journal-title":"Neuron"},{"key":"2026082709571565100_bib66","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1038\/s41559-017-0389-y","article-title":"Nemertean and phoronid genomes reveal lophotrochozoan evolution and the origin of bilaterian heads","volume":"2","author":"Luo","year":"2018","journal-title":"Nat. Ecol. Evol."},{"key":"2026082709571565100_bib67","doi-asserted-by":"publisher","first-page":"R54","DOI":"10.1186\/gb-2008-9-3-r54","article-title":"Functional diversification of duplicate genes through subcellular adaptation of encoded proteins","volume":"9","author":"Marques","year":"2008","journal-title":"Genome Biol."},{"key":"2026082709571565100_bib68","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.81613","article-title":"Peripheral and central employment of acid-sensing ion channels during early bilaterian evolution","volume":"12","author":"Mart\u00ed-Solans","year":"2023","journal-title":"Elife"},{"key":"2026082709571565100_bib69","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/nature25030","article-title":"Convergent evolution of bilaterian nerve cords","volume":"553","author":"Mart\u00edn-Dur\u00e1n","year":"2018","journal-title":"Nature"},{"key":"2026082709571565100_bib70","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1126\/science.1146317","article-title":"TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists","volume":"318","author":"Menuz","year":"2007","journal-title":"Science"},{"key":"2026082709571565100_bib71","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/s41586-025-08736-2","article-title":"GluA2-containing AMPA receptors form a continuum of Ca2+-permeable channels","volume":"641","author":"Miguez-Cabello","year":"2025","journal-title":"Nature"},{"key":"2026082709571565100_bib72","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1113\/jphysiol.1984.sp015495","article-title":"Chloride current induced by injection of calcium into Xenopus oocytes","volume":"357","author":"Miledi","year":"1984","journal-title":"J. Physiol."},{"key":"2026082709571565100_bib73","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1093\/sysbio\/syab010","article-title":"QMaker: Fast and accurate method to estimate empirical models of protein evolution","volume":"70","author":"Minh","year":"2021","journal-title":"Syst. Biol."},{"key":"2026082709571565100_bib74","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1093\/molbev\/msaa015","article-title":"IQ-TREE 2: New models and efficient methods for phylogenetic inference in the genomic era","volume":"37","author":"Minh","year":"2020","journal-title":"Mol. Biol. Evol."},{"key":"2026082709571565100_bib75","doi-asserted-by":"publisher","first-page":"108740","DOI":"10.1016\/j.neuropharm.2021.108740","article-title":"Evolution of glutamatergic signaling and synapses","volume":"199","author":"Moroz","year":"2021","journal-title":"Neuropharmacology"},{"key":"2026082709571565100_bib76","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1126\/science.7973663","article-title":"A molecular determinant for submillisecond desensitization in glutamate receptors","volume":"266","author":"Mosbacher","year":"1994","journal-title":"Science"},{"key":"2026082709571565100_bib77","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1186\/s12864-016-3215-z","article-title":"Deep sequencing of transcriptomes from the nervous systems of two decapod crustaceans to characterize genes important for neural circuit function and modulation","volume":"17","author":"Northcutt","year":"2016","journal-title":"BMC Genomics"},{"key":"2026082709571565100_bib78","doi-asserted-by":"publisher","first-page":"7496","DOI":"10.1523\/JNEUROSCI.16-23-07496.1996","article-title":"Direct measurement of AMPA receptor desensitization induced by glutamatergic synaptic transmission","volume":"16","author":"Otis","year":"1996","journal-title":"J. Neurosci."},{"key":"2026082709571565100_bib79","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.1126\/science.adf3406","article-title":"GluD1 binds GABA and controls inhibitory plasticity","volume":"382","author":"Piot","year":"2023","journal-title":"Science"},{"key":"2026082709571565100_bib80","first-page":"161","volume-title":"Methods in Enzymology","author":"Plested","year":"2021"},{"key":"2026082709571565100_bib81","doi-asserted-by":"publisher","first-page":"2682","DOI":"10.1523\/JNEUROSCI.4834-04.2005","article-title":"Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors","volume":"25","author":"Priel","year":"2005","journal-title":"J. Neurosci."},{"key":"2026082709571565100_bib82","doi-asserted-by":"publisher","first-page":"200234","DOI":"10.1098\/rsob.200234","article-title":"AMPA receptor auxiliary subunits emerged during early vertebrate evolution by neo\/subfunctionalization of unrelated proteins","volume":"10","author":"Ramos-Vicente","year":"2020","journal-title":"Open Biol."},{"key":"2026082709571565100_bib83","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.35774","article-title":"Metazoan evolution of glutamate receptors reveals unreported phylogenetic groups and divergent lineage-specific events","volume":"7","author":"Ramos-Vicente","year":"2018","journal-title":"Elife"},{"key":"2026082709571565100_bib84","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/s0092-8674(00)81734-1","article-title":"LIN-10 is a shared component of the polarized protein localization pathways in neurons and epithelia","volume":"94","author":"Rongo","year":"1998","journal-title":"Cell"},{"key":"2026082709571565100_bib85","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2313853121","article-title":"Loss of activation by GABA in vertebrate delta ionotropic glutamate receptors","volume":"121","author":"Rosano","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib86","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1016\/j.neuron.2019.08.033","article-title":"An ER assembly line of AMPA-receptors controls excitatory neurotransmission and its plasticity","volume":"104","author":"Schwenk","year":"2019","journal-title":"Neuron"},{"key":"2026082709571565100_bib87","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.neuron.2012.03.034","article-title":"High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes","volume":"74","author":"Schwenk","year":"2012","journal-title":"Neuron"},{"key":"2026082709571565100_bib88","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1126\/science.aeb3577","article-title":"Structure and organization of AMPA receptor-TARP complexes in the mammalian cerebellum","volume":"391","author":"Scrutton","year":"2026","journal-title":"Science"},{"key":"2026082709571565100_bib89","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/s0165-0173(97)00062-3","article-title":"RNA editing of brain glutamate receptor channels: Mechanism and physiology1Published on the world wide web on 5 February 1998.1","volume":"26","author":"Seeburg","year":"1998","journal-title":"Brain Res. Rev."},{"key":"2026082709571565100_bib90","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1016\/j.str.2024.04.001","article-title":"Constitutive activity of ionotropic glutamate receptors via hydrophobic substitutions in the ligand-binding domain","volume":"32","author":"Seljeset","year":"2024","journal-title":"Structure"},{"key":"2026082709571565100_bib91","doi-asserted-by":"publisher","first-page":"RP110607","DOI":"10.7554\/eLife.110607","article-title":"Are interphylum spiralian relationships resolvable?","volume":"15","author":"Serra Silva","year":"2026","journal-title":"Elife"},{"key":"2026082709571565100_bib92","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/nature11696","article-title":"Insights into bilaterian evolution from three spiralian genomes","volume":"493","author":"Simakov","year":"2013","journal-title":"Nature"},{"key":"2026082709571565100_bib93","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1038\/nature16150","article-title":"Hemichordate genomes and deuterostome origins","volume":"527","author":"Simakov","year":"2015","journal-title":"Nature"},{"key":"2026082709571565100_bib94","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1038\/s42003-025-08402-3","article-title":"Evolution of iGluR ligand specificity, polyamine regulation, and ion selectivity inferred from a placozoan epsilon receptor","volume":"8","author":"Singh","year":"2025","journal-title":"Commun. Biol."},{"key":"2026082709571565100_bib95","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/nature08624","article-title":"X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor","volume":"462","author":"Sobolevsky","year":"2009","journal-title":"Nature"},{"key":"2026082709571565100_bib96","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/0092-8674(91)90568-j","article-title":"RNA editing in brain controls a determinant of ion flow in glutamate-gated channels","volume":"67","author":"Sommer","year":"1991","journal-title":"Cell"},{"key":"2026082709571565100_bib97","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/s41576-023-00620-x","article-title":"Incongruence in the phylogenomics era","volume":"24","author":"Steenwyk","year":"2023","journal-title":"Nat. Rev. Genet."},{"key":"2026082709571565100_bib98","doi-asserted-by":"publisher","first-page":"2615","DOI":"10.1113\/JP279028","article-title":"Architecture and function of NMDA receptors: An evolutionary perspective","volume":"599","author":"Stroebel","year":"2021","journal-title":"J. Physiol."},{"key":"2026082709571565100_bib99","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/417245a","article-title":"Mechanism of glutamate receptor desensitization","volume":"417","author":"Sun","year":"2002","journal-title":"Nature"},{"key":"2026082709571565100_bib100","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1523\/jneurosci.17-01-00058.1997","article-title":"Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition","volume":"17","author":"Swanson","year":"1997","journal-title":"J. Neurosci."},{"key":"2026082709571565100_bib101","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/s41586-018-0654-5","article-title":"Shared and distinct transcriptomic cell types across neocortical areas","volume":"563","author":"Tasic","year":"2018","journal-title":"Nature"},{"key":"2026082709571565100_bib102","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1038\/s41587-021-01156-3","article-title":"SignalP 6.0 predicts all five types of signal peptides using protein language models","volume":"40","author":"Teufel","year":"2022","journal-title":"Nat. Biotechnol."},{"key":"2026082709571565100_bib103","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1038\/nature23479","article-title":"Channel opening and gating mechanism in AMPA-subtype glutamate receptors","volume":"549","author":"Twomey","year":"2017","journal-title":"Nature"},{"key":"2026082709571565100_bib104","doi-asserted-by":"publisher","first-page":"10484","DOI":"10.1073\/pnas.89.21.10484","article-title":"Glutamate receptors of Drosophila melanogaster: Cloning of a kainate-selective subunit expressed in the central nervous system","volume":"89","author":"Ultsch","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib105","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1093\/molbev\/msl197","article-title":"Evidence of interaction network evolution by whole-genome duplications: A case study in MADS-box proteins","volume":"24","author":"Veron","year":"2007","journal-title":"Mol. Biol. Evol."},{"key":"2026082709571565100_bib106","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1152\/jn.1998.79.2.555","article-title":"Functional and pharmacological differences between recombinant N-methyl-D-aspartate receptors","volume":"79","author":"Vicini","year":"1998","journal-title":"J. Neurophysiol."},{"key":"2026082709571565100_bib107","doi-asserted-by":"publisher","first-page":"148228","DOI":"10.1016\/j.ijbiomac.2025.148228","article-title":"Modular control of AMPA and Kainate receptor gating revealed by systematic domain swapping","volume":"330","author":"Vinnakota","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"2026082709571565100_bib108","doi-asserted-by":"publisher","first-page":"10781","DOI":"10.1073\/pnas.0604482103","article-title":"Reconstitution of invertebrate glutamate receptor function depends on stargazin-like proteins","volume":"103","author":"Walker","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2026082709571565100_bib109","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1038\/s41586-025-09610-x","article-title":"Delta-type glutamate receptors are ligand-gated ion channels","volume":"647","author":"Wang","year":"2025","journal-title":"Nature"},{"key":"2026082709571565100_bib110","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1016\/j.neuron.2008.07.023","article-title":"Evolutionary conserved role for TARPs in the gating of glutamate receptors and tuning of synaptic function","volume":"59","author":"Wang","year":"2008","journal-title":"Neuron"},{"key":"2026082709571565100_bib111","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.1523\/jneurosci.16-06-01982.1996","article-title":"Evidence for multiple AMPA receptor complexes in hippocampal CA1\/CA2 neurons","volume":"16","author":"Wenthold","year":"1996","journal-title":"J. Neurosci."},{"key":"2026082709571565100_bib112","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1189","article-title":"New insights into the QuikChange\u2122 process guide the use of Phusion DNA polymerase for site-directed mutagenesis","volume":"43","author":"Xia","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"2026082709571565100_bib113","doi-asserted-by":"publisher","first-page":"4209","DOI":"10.1113\/jphysiol.2011.208066","article-title":"GluA4 is indispensable for driving fast neurotransmission across a high-fidelity central synapse","volume":"589","author":"Yang","year":"2011","journal-title":"J. Physiol."},{"key":"2026082709571565100_bib118","doi-asserted-by":"publisher","first-page":"baz056","DOI":"10.1093\/database\/baz056","article-title":"LanceletDB: An integrated genome database for lancelet, comparing domain types and combination in orthologues among lancelet and other species","volume":"2019","author":"You","year":"2019","journal-title":"Database (Oxford)"},{"key":"2026082709571565100_bib114","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/s41586-021-03540-0","article-title":"Hippocampal AMPA receptor assemblies and mechanism of allosteric inhibition","volume":"594","author":"Yu","year":"2021","journal-title":"Nature"},{"key":"2026082709571565100_bib115","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.32056","article-title":"Preferential assembly of heteromeric kainate and AMPA receptor amino terminal domains","volume":"6","author":"Zhao","year":"2017","journal-title":"Elife"},{"key":"2026082709571565100_bib116","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1126\/science.adn6384","article-title":"Structural basis of odor sensing by insect heteromeric odorant receptors","volume":"384","author":"Zhao","year":"2024","journal-title":"Science"},{"key":"2026082709571565100_bib117","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1126\/science.aaw8250","article-title":"Architecture and subunit arrangement of native AMPA receptors elucidated by cryo-EM","volume":"364","author":"Zhao","year":"2019","journal-title":"Science"}],"container-title":["Journal of General Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/doi\/10.1085\/jgp.202614039\/2040323\/jgp_202614039.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jgp\/article-pdf\/doi\/10.1085\/jgp.202614039\/2040323\/jgp_202614039.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T13:57:29Z","timestamp":1787839049000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jgp\/article\/158\/6\/e202614039\/282981\/Tunable-AMPA-receptor-function-via-recurrent"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,27]]},"references-count":118,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,11,2]]}},"URL":"https:\/\/doi.org\/10.1085\/jgp.202614039","relation":{},"ISSN":["0022-1295","1540-7748"],"issn-type":[{"value":"0022-1295","type":"print"},{"value":"1540-7748","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,27]]},"article-number":"e202614039"}}