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Neurotransmitter-gated ionchannels, still front and centrestage

Derek BowieDepartment of Pharmacology andTherapeutics, McGill University, Montréal,Québec, H3G 1Y6, CanadaEmail: derek.bowie@mcgill.caEdited by: Kim Barrett

Neurotransmitter-gated ion channels arecritical for the normal hardwiring of neuro-nal circuits but also fine tune synapticstrength during periods of sustainedpatterned activity and altered homeostasis.Ionotropic glutamate receptors (iGluRs)and nicotinic acetylcholine receptors trans-mit the vast majority of fast excitatorysignalling in the developing and adultCNS whereas almost all inhibitory neuro-transmission is mediated by GABAAand glycine receptors. The study ofneurotransmitter-gated ion channelshas undergone unprecedented advances inrecent years with the convergence of severalscientific disciplines on this importantresearch topic. Structural biology hasemerged as a leading approach to under-

Correction made on 12 January 2021, afterfirst online publication: The article hasbeen updated to include the Kamalova, A &Nakagawa T. (2021) reference.

standing ion channel function and drugaction, and recent advances in geneticshave permitted different families ofneurotransmitter-gated ion channels tobe assigned to distinct roles in neuronalhealth and disease.To explore this advanced area of physio-logy, The Journal of Physiology sponsoredback-to-back 2-day conferences on thedowntown campus of McGill Universityin Montréal during the summer of 2019.The 2019 Ionotropic Glutamate ReceptorRetreat or iGluRetreat was organized byDr David Stellwagen (McGill) and myselfand follows on a tradition since 2013of holding the conference at a differentuniversity campus in North America (https://www.ion-channelconferences.org/). TheiGluRetreat brought together 25 speakerswhose work is at the forefront of thisrapidly developing field of study (Fig. 1).The 2-day International Society of Neuro-chemistry (ISN) satellite conference on‘Neurotransmitter-gated ion-channelsin health and disease’ was organized byDr Katherine Roche (NIH) and myselfand brought together a unique group ofleading researchers from across the globe toshowcase the most recent advances in thestudy of excitatory and inhibitory receptorsynapses (Fig. 2). The first day of the satelliteconference focused on the complexity ofthe ion channel signalling complex andhow structural studies have brought newadvances in drug design and therapy. Theconference’s second day examined the

emerging roles of neurotransmitter-gatedion channels in plasticity mechanisms andtheir involvement in neuronal circuits andCNS disease. This issue of The Journal ofPhysiology brings together eight timelyreview articles that capture some of theideas and discussions that arose duringthese 4 days of exciting and intense scientificdiscourse.Dr Lonnie Wollmuth and colleaguesfrom Stony Brook University discussedtheir recent work on disease-causingmutations that disrupt the functionalproperties of NMDA-type ionotropicglutamate receptors (iGluRs) (Aminet al. 2021). The Wollmuth lab has spentthe past two decades mapping out thestructure–function properties of wild-typeNMDA- and AMPA-type iGluRs. Inparticular, they have pinpointed the uniqueroles fulfilled by different subunits andevolutionarily conserved domains, suchas DRPEER (Watanabe et al. 2002) andSYTANLAAF (Jatzke et al. 2003), inchannel gating and ion permeation as wellas identifying the role of the transmembraneregion in channel tetramerization (Ganet al. 2015). This work has provided a usefulframework in which to understand theimpact of disease-causing mutations onNMDARs which, in some cases, are able tocurtail the time course of channel activationwhilst diminishing Ca2+ transport throughthe pore (Amin et al. 2018). Given the keyrole of NMDARs in neurodevelopment andplasticity (Constantine-Paton et al. 1990;

Figure 1. Photograph of the speakers and attendees at the 2019 iGluRetreat conference that wasorganized by Drs David Stellwagen (McGill) and Derek Bowie (McGill) on the downtown campus ofMcGill University

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Nicoll, 2017), the negative impact of thesemutations can be readily appreciated. Intheir review, Amin and colleagues arguethat the study of disease-causing mutationsnot only provides insight into howdefects inNMDAR function and assembly contributeto neurological disease, but also expandsour understanding of the inner workings ofNMDARs. The authors also acknowledgethat many disease mutations are foundat sites in the NMDAR that have yet tobe tied to a particular functional role. Anongoing challenge is to understand howboth gain- and loss-of-function mutationsin the NMDAR (Myers et al. 2019) can leadto neurological disease with many of thesame cardinal features.Dr David MacLean, his graduate studentMatthew Rook from Rochester University,USA and Dr Maria Musgaard fromthe University of Ottawa, Canada pre-sented work on a collaborative project ofacid-sensing ion channels (ASICs), whichhave been the focus of intense researchactivity in recent years (Rook et al. 2021).ASICs are distinguished from most otherligand-gated ion channels by their trimericsubunit stoichiometry which differs fromthe more conventional tetrameric orpentameric stoichiometry associated withiGluRs and GABAA receptors, respectively,at central synapses. First identified throughearly forays into using the concentrationclamp technique, ASICs respond to rapidmillisecond changes in extracellular pHby evoking a rapidly decaying, cationic

membrane conductance in freshly iso-lated sensory neurons (Krishtal, 2015).Since then, ASICs have been shown tobe expressed throughout the body in thecentral and peripheral nervous systemswhere they have been linked to learningand memory, pain sensation, fear andanxiety, substance abuse, and cell death.Perhaps most surprisingly, ASICs are ableto respond to rapid and brief changesin extracellular acidification (MacLean &Jayaraman, 2016)much like the rapid gatingproperties of AMPARs in response to l-Gluat auditory synapses (Joshi & Wang, 2002).Their importance to cell physiology andimplication in numerous disease states hasplaced the spotlight on ASICs and a need tobetter understand their structure–functioncharacteristics, which is the focus of thereview. An immediate challenge is tryingto understand how proton binding elicitsconformational changes in the ASICchannel structure to access the open anddesensitized states. Structural studies haveshown that each ASIC subunit consistsof a large extracellular domain, two trans-membrane helices, and short intracellular Nand C termini (Baconguis et al. 2014). Theextracellular domain has been proposed tocontain the proton binding site, although, asnoted by the authors, its role in the processof channel activation and desensitizationis still debated. Aided by recent full-lengthstructures of ASIC channels (e.g. Yoderet al. 2018), Rook and colleagues haverecently developed a working model of how

ASIC1 channels enter into and out of thedesensitized state(s) using a combination offast perfusion electrophysiology, moleculardynamic simulations and crosslinkingexperiments (Rook et al. 2020). Their workunexpectedly highlights the importance ofthe β11-12 linker connecting the proposedextracellular proton binding pocket withtransmembrane helices as being a keyregulator of channel desensitization.Despite all these advances, the authorsreflect on the challenges in studying gatingevents promoted by proton binding butoffer some insights for the way forward forthis important area of ion channel biology.Dr Anthony Koleske and graduate student

Juliana Shaw from Yale University alsodiscussed the role of NMDARs andquestioned exactly how they couple tothe cell’s cytoskeleton (Shaw & Koleske,2021). The idea that NMDARs are linked tothe cytoskeleton was first appreciated fromexperiments showing that the inactivationof NMDARs, which occurs due to thetransport of Ca2+ through the channelpore, could be blocked by agents that pre-vent actin depolymerization (Rosenmund& Westbrook, 1993). This finding linkingchannel activity to the cell’s architecturalproteins was further supported by workshowing that NMDARs were, in fact,mechanosensitive (Paoletti & Ascher,1994). Direct biochemical evidence wasestablished by using latrunculin-A toinduce actin depolymerization, whichdispersed NMDARs from synaptic sites

Figure 2. The speakers and attendees at the 2019 ISN satellite conference on ‘Neurotransmitter-gatedion-channels in health and disease’ that was organized by Drs Katherine Roche (NIH) and Derek Bowie(McGill) on the downtown campus of McGill University

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(Allison et al. 1998) through its inter-action with α-actinin-2, which binds to thecytoplasmic tails of GluN1 and GluN2BNMDAR subunits (Wyszynski et al. 1997).In their review article, Shaw and Koleskedescribe the mechanisms by which actinregulates the functional properties ofdifferent voltage- and ligand-gated channelfamilies with an emphasis on the regulationof NMDARs (Shaw & Koleske, 2021).Previous work from the Koleske lab hasestablished the importance of dynamicactin networks in regulating NMDARfunction at central synapses in Noonansyndrome (Levy et al. 2018), a multi-systemdisorder characterized by developmentaldelay and learning difficulties (Robertset al. 2013). Noonan syndrome is causedby hyperactivating mutations in the SHP2tyrosine phosphatase which disrupt thephosphorylated tyrosine binding site onthe GluN2B cytoplasmic tail for the Nck2adaptor protein. This phosphorylationevent is detrimental in Noonan syndromesince it disrupts the partnership of Nck2with N-WASp, which activate actin branchnucleation via the Arp2/3 complex(Levy et al. 2018). The untethering ofNck2 selectively impairs GluN2B NMDARfunctionality at Schaffer collateral–CA1neuron excitatory synapses inducingdeficits in long-term potentiation (Levyet al. 2018). The authors conclude byspeculating on why NMDARs may coupleto the cytoskeleton via actin, suggestingthat the interaction may be importantin the gating properties of NMDARs.Since alterations in the intrinsic disorderof the cytoplasmic tail of NMDARs, byphosphorylation for example, impactchannel functionality (Choi et al. 2011,2013), it is clear that more work is neededto better understand how these molecularevents impact neuronal communicationand ultimately contribute to CNS disease.The review article by Drs KatherineRoche and Sehoon Won from theNational Institutes of NeurologicalDisorders and Stroke in Bethesda, MDhighlights the important balancing roleof striatal-enriched tyrosine phosphatase61 (STEP61) at glutamatergic synapses(Won & Roche, 2021). The strength ofsignalling at glutamatergic synapses isstrongly regulated by phosphorylationevents driven by the actions of a numberof serine and tyrosine kinases (Chen &Roche, 2007). The NMDAR, in particular,is targeted by a family of src tyrosinekinases, which includes Src and Fyn, which

upregulate channel activity and contributeto long-term potentiation in the CA1 regionof the hippocampus (Salter & Kalia, 2004).Tyrosine phosphatases, such as STEP, arethus important in regulating the balanceat central synapses. The most abundantisoform in the brain is STEP61, whichhas garnered a lot of attention due to itsimplicated roles in neurological disease(Goebel-Goody et al. 2012). STEP61 hasa number of synaptic targets includingtyrosine kinase Fyn and NMDA- andAMPA-type ionotropic glutamate receptors(Won et al. 2016, 2019). Fyn and Srckinases phosphorylate NMDARs on severaltyrosine residues in the cytoplasmic tail ofthe GluN2A and GluN2B subunits. Amongthese tyrosine residues, Y1472 is adjacentto the PSD-95 binding site, which whenphosphorylated inhibits clathrin-mediatedendocytosis of GluN2B-containingNMDARs. STEP61 targets GluN2BY1472 for dephosphorylation and inter-nalization. Although AMPARs have shortercytoplasmic tails, phosphorylation anddephosphorylation events by numerouskinases and phosphatases similarlyregulate receptor trafficking, endocytosisand synaptic plasticity. For example,phosphorylation of Y876 in the cyto-plasmic tail of the GluA2 subunit disruptsGRIP1/2 binding leaving PICK1 bound,which promotes internalization of AMPARs(Hayashi & Huganir, 2004). STEP61 wasrecently shown by mass spectrometry tobind directly to the cytoplasmic tails ofthe GluA2 and A3 subunits but not theGluA1 subunit. Accordingly, expressionof GluA2 and GluA3 subunits at synapsesis increased in STEP-KO mouse brainwhereas STEP61 overexpression reduces thesynaptic expression and responsiveness ofAMPARs (Won et al. 2019). The authorsconclude by reviewing the evidence linkingan upregulation in the expression of STEP61in cognitive impairment associated withageing reported in several rodent, rhesusmonkey and human studies suggestingthat STEP61 inhibitors, such as TC-2153(Xu et al. 2014), may be a valuable form oftreatment.The article by Dr Teru Nakagawa andgraduate student Aichurok Kamalovafrom Vanderbilt University provides atimely review of the multifaceted natureof the AMPA receptor–auxiliary subunitcomplex (Kamalova & Nakagawa, 2021).An early cryo-EM study gave us our firstglimpse of the complex nature by whichtransmembrane AMPA receptor auxiliary

proteins (TARPs) affect receptor functionby bracing the transmembrane domainsof the ion channel pore region (Nakagawaet al. 2005). Since then, several labs haveprovided an even greater picture of theseinteractions by studying full-length homo-and heteromeric structures of the AMPARin complex with γ 2 and γ 8 TARPs, germcell-specific gene 1-like protein (GSG1L;Greger et al. 2017; Chen & Gouaux, 2019;Twomey et al. 2019) and more recently,in association with cornichon-3 (CNIH3;Nakagawa, 2019). It is becoming clear thatnative AMPARs co-assemble with a numberof different auxiliary subunit families,which has made it imperative to betterunderstand how these associations affectbrain function. The review focuses on theemerging evidence suggesting that differentfamilies of auxiliary subunits interact withAMPARs in different ways, explainingtheir distinct effects on ion channel gatingand ion-permeation. The slower gatingbehaviour of the AMPAR–TARP complexcan be explained by TARP interactionswith the KGK site (Dawe et al. 2016) of theligand-binding domain of AMPARs as wellas residues located in the transmembraneregions (Ben-Yaacov et al. 2017; Hawkenet al. 2017). GSG1L has a similar overallarchitecture to TARPs and it is thoughtto interact with AMPARs in a similarmanner (Twomey et al. 2017), yet it lacksan extracellular helix found in TARPsand possesses a larger β1–β2 loop. Theauthors argue that these distinctions explainwhy TARPs preferentially slow entry intodesensitization whereas GSG1L slowsrecovery, although the exact details remainto be resolved. The recent structure ofthe AMPAR–CNIH3 complex reveals thatcornichons contain four transmembraneregions, not three as originally proposed,and lack the extensive extracellular domainsthat are so critical for TARP and GSG1Lfunction (Nakagawa, 2019). Consequently,the modulatory effects of CNIHs thatslow AMPAR channel gating and relievepolyamine channel block are presumablymediated by residues in the transmembranedomain. Details are still emerging, but itmay suggest that the structural events thatregulate channel gating and ion permeationare perhaps functionally coupled. What isclear is that the coming years will provide afuller understanding of the structural andfunctional nature of the AMPAR–auxiliarysubunit complex and how it shapes thephysiology of neuronal circuits and disruptsthem in neurological disease.

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Drs Jakob von Engelhardt and EricJacobi from the Johannes GutenbergUniversity Mainz, Germany also discussthe importance of the AMPAR–auxiliarysubunit complex but focus on its criticalrole in shaping the strength and fidelityof synaptic communication as well asits impact on the signalling capacity ofneuronal circuits (Jacobi & von Engelhardt,2021). AMPARs co-assemble with threemajor auxiliary subunit families, includingmembers of the claudin family (TARPsγ 2-5 and γ 7-8 as well as GSG1L), theCKAMP family (CKAMP39, -44, -52 and-59) and the cornichons (CNIH2 and -3),most of which facilitate the traffickingand synaptic localization of AMPARs inneurons. Knockout mice or overexpressionstudies reveal that auxiliary proteinsalso impact the gating and permeationproperties of native AMPARs. The TARP,CKAMP and CNIH families are, however,differentially expressed in the mammalianbrain (Schwenk et al. 2014) suggesting thatsignalling in different brain regions maybe finely tuned by their expression pattern.For example, TARP γ 8 and CNIH2 are pre-dominantly expressed in the hippocampus,cortex and striatum (Schwenk et al. 2014),with CKAMP44 and GSG1L primarilyexpressed in glutamatergic neurons of thecortex (Zeisel et al. 2018). The authorsdiscuss how most auxiliary subunitsincrease the strength of glutamatergicsynapses through a number of mechanismsthat include increasing channel densityand augmenting open channel probabilityand/or its unitary conductance. Theexception to this is GSG1L, which has beenshown to decrease channel density andunitary conductance in the cerebellumand hippocampus (McGee et al. 2015;Gu et al. 2016). The von Engelhardt labhas provided compelling evidence tosupport the important role of CKAMP44 ingoverning short-term plasticity of granulecells in the dentate gyrus (von Engelhardtet al. 2010; Khodosevich et al. 2014)and relay neurons in the dorsal lateralgeniculate nucleus (Chen et al. 2018), withother groups similarly establishing theimportance of CKAMP52 in CA1 neuronsof the hippocampus andPurkinje cells of thecerebellum (Klaassen et al. 2016; Peter et al.2020). The review concludes by discussingthe extensive literature on the importantrole fulfilled by TARP γ 2 and γ 8 inlong-term potentiation in the hippocampusand the paucity of information on howAMPAR auxiliary subunits affect homeo-

static plasticity. The greater understandingof the AMPAR–auxiliary subunit complexand the role it plays in neuronal circuits andultimately in human behaviour and diseasemay lead to breakthrough strategies of drugdesign that target the complex and notsimply the channel pore forming subunits(Rosenbaum et al. 2020).Drs Melanie Woodin and Jessica Presseyfrom the University of Toronto reviewthe unexpectedly diverse mechanismsby which native kainate-type (KARs)ionotropic glutamate receptors signal atdifferent synapses in the hippocampus(Pressey & Woodin, 2021). Unlike thecanonical view of AMPARs and NMDARs,it has been much more difficult to assigngeneral guiding principles to how KARssignal at central synapses. A major break-through was the appreciation that theselective, non-competitive block by severalGYKI compounds of the much largerAMPAR response revealed the smalleramplitude, slower decaying responses ofsynaptic KARs (Paternain et al. 1995).With this research tool at hand and withgenetic knockout strategies, it has beenpossible to pinpoint KARs to both thepre- and postsynaptic sides of excitatoryglutamatergic and inhibitory GABAergicsynapses (Contractor et al. 2011). Asoutlined by the authors, a significantsurprise has been the understanding thatKARs not only signal via an ionotropicpathway but also regulate the activity ofvoltage-gated potassium (Melyan et al.2002) and calcium (Rodriguez-Moreno &Lerma, 1998) channels via a metabotropicG-protein coupled pathway. The Woodinlab has added further complexity to theKAR signalling profile by linking theiractivity to that of the neuron-specificK+–Cl− co-transporter, KCC2 (Pre-ssey et al. 2017). Since KCC2 sets thechloride equilibrium potential in matureneurons (Kaila et al. 2014), it ultimatelydetermines the strength of GABAergicneurotransmission. The indirect regulatoryeffect of KARs on KCC2 is mediated bythe KAR auxiliary protein, Neto2, whichnot only binds and regulates the gatingand permeation properties of KARs butalso binds directly to KCC2 (Ivakineet al. 2013; Mahadevan et al. 2014). Theimportance of this interaction can beappreciated from the behavioural analysisof Neto2 KO mice, which have a reducedthreshold for seizures through the lossof KCC2 and diminished GABAergicneurotransmission (Mahadevan et al.

2015). Whether dysfunction of the newlydiscovered KAR–Neto2–KCC2 complexplays a role in CNS disease awaits to beuncovered.Last but certainly not least, Drs Stephen

Glasgow, Ed Ruthazer and Tim Kennedyfrom the Montreal Neurological Institute ofMcGill University provide a comprehensivereview of their work highlighting thesignificant role of netrin-1 in synapticplasticity and memory consolidation inthe adult brain (Glasgow et al. 2021).Netrins were originally identified aschemoattractant guidance cues duringembryogenesis that direct cell and axonmigration (Kennedy & Tessier-Lavigne,1995). However, netrins continue to beexpressed by neurons into adulthoodopening the question of whether theyadopt different roles in mature neuronalcircuits. The authors open their reviewby noting that many of the signallingcascades that are activated during changesin synaptic plasticity in the adult brainare similar to the cascade of signallingevents triggered by chemotropic axonguidance cues during development. Thefirst clue to understanding this puzzle wasthe observation that genetic deletion ofthe canonical receptor for netrin-1, thesingle-pass transmembrane protein calleddeleted in colorectal cancer (DCC) resultsin the loss of hippocampal long-termpotentiation and impairment of spatialand recognition memory (Horn et al.2013). Their next findings revealed thatthe ligand, Netrin-1, promotes excitatorysynaptogenesis between cortical neuronsby initiating synapse assembly and contactpoints, which increases the efficacy ofexcitatory synaptic transmission (Goldmanet al. 2013). More details of this mechanismemerged with the finding that membranedepolarization and NMDAR activation atcentral synapses promotes the secretionof netrin-1 from dendrites (Glasgowet al. 2018). In agreement with theirearlier findings with DCC deletion, theauthors show that netrin-1 expression byhippocampal CA1 pyramidal neurons isrequired forNMDAR-dependent long-termpotentiation (Glasgow et al. 2018). In fact,the exogenous application of netrin-1 isenough to trigger the potentiation of CA1neuron glutamatergic synapses with theinsertion of GluA1-containing AMPARsmediated through a rise in cytosolic Ca2+(Glasgow et al. 2018). This surprising yetrational alignment between molecularevents in embryogenesis and the signalling

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and structural processes that give rise tolong-term potentiation in the adult brainreveals a remarkable economy in how theneurons are able to find different uses forprocesses with quite distinct purposes.Much is still to be uncovered about the roleof netrin-1 in the adult brain though morerecent work highlighting its role in spatialmemory formation (Wong et al. 2019) andthe specific pre- and postsynaptic role ofits receptor, DCC (Glasgow et al. 2020),suggest that a fuller understanding may beforthcoming.It has been more than three decades sincethe first cloning studies began to reveal themolecular identity of the neurotransmitterreceptors that populate glutamatergic andGABAergic synapses in the mammalianbrain (Schofield et al. 1987; Hollmannet al. 1989). Since then, genetic knockoutand knockin studies have helped pinpointthe distribution and synaptic roles ofiGluRs and GABAA receptors and refinean understanding of their roles in synaptictransmission and plasticity mechanisms.With many full-length homomeric andheteromeric structures of pore-formingsubunits iGluRs and GABAA receptorsreported in the last decade (Sobolevsky et al.2009; Miller & Aricescu, 2014), our nextsteps will be to understand the structuralbiology of the synapse in its entirety. Thisis needed if we are to appreciate howauxiliary subunits and signalling proteins,such as kinases and phosphatases, coupleto ion channels and regulate excitatoryand inhibitory neurotransmission inthe brain. The cell- and region-specificexpression pattern of auxiliary subunits inthe developing and adult brain (Zeisel et al.2018) also offers an opportunity for moretargeted neuropharmacology that exploitstheir unique protein–protein interactionsto develop drugs with more specificity andfewer side effects (Rosenbaum et al. 2020).Together with the strident advances insystems biology, the next decade looks setto provide for the first time a comprehensiveunderstanding of how molecular events atthe synapse and within neuronal circuitsgive rise to complex animal and humanbehaviour and go awry in neurologicaldisease.

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Additional information

Competing interests

No competing interests declared.

Author contributions

Sole author.

Funding

The author received funding from CIHR: FRN162317 and FRN 142431.

Keywords

AMPA receptor, ASIC channels, ion channels,GABA receptor, kainate receptor, NMDAreceptor, synapse, synaptic plasticity

© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society