Kainate Receptors in Health and Disease
2013; Cell Press; Volume: 80; Issue: 2 Linguagem: Inglês
10.1016/j.neuron.2013.09.045
ISSN1097-4199
Autores Tópico(s)Glycosylation and Glycoproteins Research
ResumoOur understanding of the molecular properties of kainate receptors and their involvement in synaptic physiology has progressed significantly over the last 30 years. A plethora of studies indicate that kainate receptors are important mediators of the pre- and postsynaptic actions of glutamate, although the mechanisms underlying such effects are still often a topic for discussion. Three clear fields related to their behavior have emerged: there are a number of interacting proteins that pace the properties of kainate receptors; their activity is unconventional since they can also signal through G proteins, behaving like metabotropic receptors; they seem to be linked to some devastating brain diseases. Despite the significant progress in their importance in brain function, kainate receptors remain somewhat puzzling. Here we examine discoveries linking these receptors to physiology and their probable implications in disease, in particular mood disorders, and propose some ideas to obtain a deeper understanding of these intriguing proteins. Our understanding of the molecular properties of kainate receptors and their involvement in synaptic physiology has progressed significantly over the last 30 years. A plethora of studies indicate that kainate receptors are important mediators of the pre- and postsynaptic actions of glutamate, although the mechanisms underlying such effects are still often a topic for discussion. Three clear fields related to their behavior have emerged: there are a number of interacting proteins that pace the properties of kainate receptors; their activity is unconventional since they can also signal through G proteins, behaving like metabotropic receptors; they seem to be linked to some devastating brain diseases. Despite the significant progress in their importance in brain function, kainate receptors remain somewhat puzzling. Here we examine discoveries linking these receptors to physiology and their probable implications in disease, in particular mood disorders, and propose some ideas to obtain a deeper understanding of these intriguing proteins. Most excitatory synapses in the brain use the amino acid glutamate as a neurotransmitter. Since the excitatory properties of glutamate were postulated nearly 40 years ago, an extraordinary wealth of data has accumulated on the types of synaptic responses triggered by this neurotransmitter. Glutamate acts on a variety of receptor proteins, initially classified by the mechanisms that they use to transmit signals (i.e., metabotropic versus ionotropic). A more precise specification of ionotropic receptors into three types was subsequently proposed, based on the agonist that activates or binds to them. Thus, AMPA, kainate, and NMDA receptors (AMPARs, KARs, and NMDARs, respectively) are recognized as the main effectors of glutamate at synapses. We now know that this classification is misleading, since there is certain cross-reactivity between agonists and receptors and only recently have some new compounds enriched the pharmacological armamentarium (see Jane et al., 2009Jane D.E. Lodge D. Collingridge G.L. Kainate receptors: pharmacology, function and therapeutic potential.Neuropharmacology. 2009; 56: 90-113Crossref PubMed Scopus (111) Google Scholar for a review). Unlike other receptors, studies of KARs suffered from the lack of specific compounds to activate or block these proteins. First of all, kainate is derived from the seaweed known as “kaininso” in Japanese, and it is a mixed agonist that can also activate AMPARs. This fact led to certain misinterpretations of the role of KARs in the brain and, even nowadays, some related errors can be detected in the literature. In addition, the prototypical AMPAR agonist, AMPA, can also activate diverse KARs. Like the AMPARs and NMDARs, KARs are tetrameric combinations of a number of subunits: named GluK1, GluK2, GluK3, GluK4, and GluK5 (previously known as GluR5–GluR7 and KA1 and KA2, respectively). Of these, GluK1–GluK3 may form functional homomeric or heteromeric receptors, while GluK4 and GluK5 only participate in functional receptors when partnering any of the GluK1–GluK3 subunits. The structural repertoire of KAR subtypes is further extended by editing of the GluK1 and GluK2 receptor subunit pre-mRNAs at the so-called Q/R site of the second membrane domain. More isoforms also arise from the alternative splicing of GluK1–GluK3 subunits, while GluK4 and GluK5 seem not to be subjected to this type of processing. The absence of specific antibodies against different KAR subunits has been a significant limitation in terms of exploring receptor distribution. Thus, most of the information regarding their tissue expression comes from in situ hybridization studies that, although informative, cannot reveal the subcellular distribution of a given subunit. Relatively good and specific antisera against the KAR subunits GluK2/3 and GluK5 are now available, although not all work properly in immunocytochemistry. Nevertheless, some general rules could be extracted from all these studies. GluK2 subunits are mostly expressed by principal cells (hippocampal pyramidal cells; both hippocampal and cerebellar granule cells; cortical pyramidal cells), while GluK1 is mainly present in hippocampal and cortical interneurons (Paternain et al., 2003Paternain A.V. Cohen A. Stern-Bach Y. Lerma J. A role for extracellular Na+ in the channel gating of native and recombinant kainate receptors.J. Neurosci. 2003; 23: 8641-8648PubMed Google Scholar) as well as in Purkinje cells and sensory neurons. GluK3 is poorly expressed, appearing in layer IV of the neocortex and dentate gyrus in the hippocampus (Wisden and Seeburg, 1993Wisden W. Seeburg P.H. A complex mosaic of high-affinity kainate receptors in rat brain.J. Neurosci. 1993; 13: 3582-3598Crossref PubMed Google Scholar). GluK4 is mainly expressed in CA3 pyramidal neurons, dentate gyrus, neocortex, and Purkinje cells, while GluK5 is expressed abundantly in the brain (Bahn et al., 1994Bahn S. Volk B. Wisden W. Kainate receptor gene expression in the developing rat brain.J. Neurosci. 1994; 14: 5525-5547Crossref PubMed Google Scholar). The functional description of KARs within the CNS (Lerma et al., 1993Lerma J. Paternain A.V. Naranjo J.R. Mellström B. Functional kainate-selective glutamate receptors in cultured hippocampal neurons.Proc. Natl. Acad. Sci. USA. 1993; 90: 11688-11692Crossref PubMed Scopus (172) Google Scholar) and the molecular identification of KAR subunits represented real breakthroughs in the study of these receptors, as did the discovery that GYKI53655, a 2,3, benzodiazepine, was essentially inactive at KARs (Paternain et al., 1995Paternain A.V. Morales M. Lerma J. Selective antagonism of AMPA receptors unmasks kainate receptor-mediated responses in hippocampal neurons.Neuron. 1995; 14: 185-189Abstract Full Text PDF PubMed Scopus (294) Google Scholar, Wilding and Huettner, 1995Wilding T.J. Huettner J.E. Differential antagonism of alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid-preferring and kainate-preferring receptors by 2,3-benzodiazepines.Mol. Pharmacol. 1995; 47: 582-587PubMed Google Scholar) (with the exception of a few particular assemblies on which it may act at high concentrations; see Perrais et al., 2009Perrais D. Pinheiro P.S. Jane D.E. Mulle C. Antagonism of recombinant and native GluK3-containing kainate receptors.Neuropharmacology. 2009; 56: 131-140Crossref PubMed Scopus (41) Google Scholar), and constitute the foundation upon which our understanding of KARs has been constructed. On the basis of the data collected over the last 30 years of research, how do we now envisage the physiological role of KARs? A comprehensive analysis of the profuse yet often controversial literature on KARs leads us to conclude that these receptors play significant roles in the brain at three main levels. In the first place, they mediate postsynaptic depolarization and they are responsible for carrying some of the synaptic current, although this only happens at some synapses. Second, KARs can modulate the synaptic release of neurotransmitters such as GABA and glutamate at different sites. Third, they play an influential role in the maturation of neural circuits during development. These roles are frequently fulfilled in an unconventional way given that KARs can signal by activating a G protein, behaving more like a metabotropic receptor than an ion channel. This noncanonical signaling is totally unexpected considering that the three iGluRs share a common molecular design, as recently revealed by their crystal structure (Mayer, 2005Mayer M.L. Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity.Neuron. 2005; 45: 539-552Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, Furukawa et al., 2005Furukawa H. Singh S.K. Mancusso R. Gouaux E. Subunit arrangement and function in NMDA receptors.Nature. 2005; 438: 185-192Crossref PubMed Scopus (322) Google Scholar, Gouaux, 2004Gouaux E. Structure and function of AMPA receptors.J. Physiol. 2004; 554: 249-253Crossref PubMed Scopus (86) Google Scholar). It is difficult to do justice to the literature generated on KARs over the years in the short space available, and indeed, there are several reviews that have described many of the molecular, biophysical, pharmacological, and functional aspects of these receptors (Rodrigues and Lerma, 2012Rodrigues R.J. Lerma J. Metabotropic signaling by kainate receptors.WIREs: Membrane Transport and Signaling. 2012; 1: 399-410Crossref Scopus (3) Google Scholar, Contractor et al., 2011Contractor A. Mulle C. Swanson G.T. Kainate receptors coming of age: milestones of two decades of research.Trends Neurosci. 2011; 34: 154-163Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, Lerma et al., 2001Lerma J. Paternain A.V. Rodríguez-Moreno A. López-García J.C. Molecular physiology of kainate receptors.Physiol. Rev. 2001; 81: 971-998Crossref PubMed Google Scholar, Lerma, 2003Lerma J. Roles and rules of kainate receptors in synaptic transmission.Nat. Rev. Neurosci. 2003; 4: 481-495Crossref PubMed Scopus (208) Google Scholar, Lerma, 2006Lerma J. Kainate receptor physiology.Curr. Opin. Pharmacol. 2006; 6: 89-97Crossref PubMed Scopus (112) Google Scholar, Copits and Swanson, 2012Copits B.A. Swanson G.T. Dancing partners at the synapse: auxiliary subunits that shape kainate receptor function.Nat. Rev. Neurosci. 2012; 13: 675-686PubMed Google Scholar, Vincent and Mulle, 2009Vincent P. Mulle C. Kainate receptors in epilepsy and excitotoxicity.Neuroscience. 2009; 158: 309-323Crossref PubMed Scopus (83) Google Scholar, Coussen and Mulle, 2006Coussen F. Mulle C. Kainate receptor-interacting proteins and membrane trafficking.Biochem. Soc. Trans. 2006; 34: 927-930Crossref PubMed Scopus (15) Google Scholar, Pinheiro and Mulle, 2006Pinheiro P. Mulle C. Kainate receptors.Cell Tissue Res. 2006; 326: 457-482Crossref PubMed Scopus (144) Google Scholar, Tomita and Castillo, 2012Tomita S. Castillo P.E. Neto1 and Neto2: auxiliary subunits that determine key properties of native kainate receptors.J. Physiol. 2012; 590: 2217-2223Crossref PubMed Scopus (13) Google Scholar, Jaskolski et al., 2005Jaskolski F. Coussen F. Mulle C. Subcellular localization and trafficking of kainate receptors.Trends Pharmacol. Sci. 2005; 26: 20-26Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, Matute, 2011Matute C. Therapeutic potential of kainate receptors.CNS Neurosci. Ther. 2011; 17: 661-669Crossref PubMed Scopus (12) Google Scholar). Hence, in this Review we will focus primarily on the data that have influenced our notion of KAR function and the wealth of new data available implicating KARs in brain pathology. To date, and like many other receptors and channels, a whole set of proteins have been identified that can interact with KAR subunits (Table 1). Indeed, the identification of these proteins has changed our view on how KARs function and provided insight into the discrepancies between native and recombinant KAR properties. While the exact role of these interactions still remains to be unambiguously established, the role of KARs in physiology will be difficult to understand without taking into account the contribution of these proteins. For instance, KARs and many of these proteins seem to undergo transient interactions that promote receptor trafficking, regulating their surface expression. PDZ motif-containing proteins such as postsynaptic density protein 95 (PSD-95), protein interacting with C kinase-1 (PICK1), and glutamate receptor interacting protein (GRIP) seem to be relevant for the stabilization of KARs at the synaptic membrane (Hirbec et al., 2003Hirbec H. Francis J.C. Lauri S.E. Braithwaite S.P. Coussen F. Mulle C. Dev K.K. Coutinho V. Meyer G. Isaac J.T.R. et al.Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP.Neuron. 2003; 37: 625-638Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). However, PDZ-binding motifs in the C terminus of KAR subunits are also present in other glutamate receptors. Thus, these interacting proteins are not selective for KARs. Although interactions with PDZ domains cannot entirely account for the subcellular distribution of KARs, the interaction with PDZ proteins produce apparently different outcomes for these receptors, as these proteins prevent AMPAR internalization but facilitate KAR internalization (Hirbec et al., 2003Hirbec H. Francis J.C. Lauri S.E. Braithwaite S.P. Coussen F. Mulle C. Dev K.K. Coutinho V. Meyer G. Isaac J.T.R. et al.Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP.Neuron. 2003; 37: 625-638Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar).Table 1The Kainate Receptor InteractomeInteractorKAR SubunitDirectRoleReferencesActinfilinGluK2YesReceptor degradation through ubiquitinationSalinas et al., 2006Salinas G.D. Blair L.A.C. Needleman L.A. Gonzales J.D. Chen Y. Li M. Singer J.D. Marshall J. Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway.J. Biol. Chem. 2006; 281: 40164-40173Crossref PubMed Scopus (43) Google Scholarβ-cateninGluK2NoPlasma membrane dynamicsCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarCadherinGluK2NDReceptor trafficking/subcellular localizationCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarCalcineurinGluK2YesCa2+-regulation of channel functionCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarCalmodulinGluK2YesNDCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarContactinGluK2YesNDCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarCOPIGluK5YesReceptor traffickingVivithanaporn et al., 2006Vivithanaporn P. Yan S. Swanson G.T. Intracellular trafficking of KA2 kainate receptors mediated by interactions with coatomer protein complex I (COPI) and 14-3-3 chaperone systems.J. Biol. Chem. 2006; 281: 15475-15484Crossref PubMed Scopus (30) Google ScholarDynamin-1GluK2YesNDCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarDynamitinGluK2YesNDCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar14.3.3GluK1, GluK2, GluK5YesReceptor traffickingCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, Vivithanaporn et al., 2006Vivithanaporn P. Yan S. Swanson G.T. Intracellular trafficking of KA2 kainate receptors mediated by interactions with coatomer protein complex I (COPI) and 14-3-3 chaperone systems.J. Biol. Chem. 2006; 281: 15475-15484Crossref PubMed Scopus (30) Google Scholar4.1NGluK1, GluK2YesReceptor traffickingCopits and Swanson, 2013bCopits B.A. Swanson G.T. Kainate receptor post-translational modifications differentially regulate association with 4.1N to control activity-dependent receptor endocytosis.J. Biol. Chem. 2013; 288: 8952-8965Crossref PubMed Scopus (5) Google ScholarGRIPGluK2, K5YesReceptor traffickingHirbec et al., 2003Hirbec H. Francis J.C. Lauri S.E. Braithwaite S.P. Coussen F. Mulle C. Dev K.K. Coutinho V. Meyer G. Isaac J.T.R. et al.Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP.Neuron. 2003; 37: 625-638Abstract Full Text Full Text PDF PubMed Scopus (127) Google ScholarKRIP6GluK2YesReceptor gatingLaezza et al., 2007Laezza F. Wilding T.J. Sequeira S. Coussen F. Zhang X.Z. Hill-Robinson R. Mulle C. Huettner J.E. Craig A.M. KRIP6: a novel BTB/kelch protein regulating function of kainate receptors.Mol. Cell. Neurosci. 2007; 34: 539-550Crossref PubMed Scopus (25) Google ScholarNETO1GluK1-3YesIon channel functionZhang et al., 2009Zhang W. St-Gelais F. Grabner C.P. Trinidad J.C. Sumioka A. Morimoto-Tomita M. Kim K.S. Straub C. Burlingame A.L. Howe J.R. Tomita S. A transmembrane accessory subunit that modulates kainate-type glutamate receptors.Neuron. 2009; 61: 385-396Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, Copits et al., 2011Copits B.A. Robbins J.S. Frausto S. Swanson G.T. Synaptic targeting and functional modulation of GluK1 kainate receptors by the auxiliary neuropilin and tolloid-like (NETO) proteins.J. Neurosci. 2011; 31: 7334-7340Crossref PubMed Scopus (33) Google Scholar, Straub et al., 2011aStraub C. Hunt D.L. Yamasaki M. Kim K.S. Watanabe M. Castillo P.E. Tomita S. Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1.Nat. Neurosci. 2011; 14: 866-873Crossref PubMed Scopus (39) Google Scholar, Tang et al., 2011Tang M. Pelkey K.A. Ng D. Ivakine E. McBain C.J. Salter M.W. McInnes R.R. Neto1 is an auxiliary subunit of native synaptic kainate receptors.J. Neurosci. 2011; 31: 10009-10018Crossref PubMed Scopus (26) Google ScholarNETO2GluK1-3YesIon channel functionZhang et al., 2009Zhang W. St-Gelais F. Grabner C.P. Trinidad J.C. Sumioka A. Morimoto-Tomita M. Kim K.S. Straub C. Burlingame A.L. Howe J.R. Tomita S. A transmembrane accessory subunit that modulates kainate-type glutamate receptors.Neuron. 2009; 61: 385-396Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, Copits et al., 2011Copits B.A. Robbins J.S. Frausto S. Swanson G.T. Synaptic targeting and functional modulation of GluK1 kainate receptors by the auxiliary neuropilin and tolloid-like (NETO) proteins.J. Neurosci. 2011; 31: 7334-7340Crossref PubMed Scopus (33) Google ScholarNSFGluK2YesNDCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarPICK1GluK2, GluK5YesReceptor traffickingHirbec et al., 2003Hirbec H. Francis J.C. Lauri S.E. Braithwaite S.P. Coussen F. Mulle C. Dev K.K. Coutinho V. Meyer G. Isaac J.T.R. et al.Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP.Neuron. 2003; 37: 625-638Abstract Full Text Full Text PDF PubMed Scopus (127) Google ScholarProfillin IIGluK2YesReceptor traffickingCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, Mondin et al., 2010Mondin M. Carta M. Normand E. Mulle C. Coussen F. Profilin II regulates the exocytosis of kainate glutamate receptors.J. Biol. Chem. 2010; 285: 40060-40071Crossref PubMed Scopus (8) Google ScholarPSD95GluK2, GluK5YesAlters receptor function by reducing desensitizationGarcia et al., 1998Garcia E.P. Mehta S. Blair L.A. Wells D.G. Shang J. Fukushima T. Fallon J.R. Garner C.C. Marshall J. SAP90 binds and clusters kainate receptors causing incomplete desensitization.Neuron. 1998; 21: 727-739Abstract Full Text Full Text PDF PubMed Scopus (194) Google ScholarSAP102GluK2, GluK5YesReceptor clustering;Garcia et al., 1998Garcia E.P. Mehta S. Blair L.A. Wells D.G. Shang J. Fukushima T. Fallon J.R. Garner C.C. Marshall J. SAP90 binds and clusters kainate receptors causing incomplete desensitization.Neuron. 1998; 21: 727-739Abstract Full Text Full Text PDF PubMed Scopus (194) Google ScholarSAP90GluK2, GluK5YesReceptor clustering; modulation of desensitizationGarcia et al., 1998Garcia E.P. Mehta S. Blair L.A. Wells D.G. Shang J. Fukushima T. Fallon J.R. Garner C.C. Marshall J. SAP90 binds and clusters kainate receptors causing incomplete desensitization.Neuron. 1998; 21: 727-739Abstract Full Text Full Text PDF PubMed Scopus (194) Google ScholarSAP97GluK2YesReceptor clusteringGarcia et al., 1998Garcia E.P. Mehta S. Blair L.A. Wells D.G. Shang J. Fukushima T. Fallon J.R. Garner C.C. Marshall J. SAP90 binds and clusters kainate receptors causing incomplete desensitization.Neuron. 1998; 21: 727-739Abstract Full Text Full Text PDF PubMed Scopus (194) Google ScholarSNAP25GluK5NDReceptor traffickingSelak et al., 2009Selak S. Paternain A.V. Aller M.I. Picó E. Rivera R. Lerma J. A role for SNAP25 in internalization of kainate receptors and synaptic plasticity.Neuron. 2009; 63: 357-371Abstract Full Text Full Text PDF PubMed Scopus (35) Google ScholarSpectrinGluK2YesNDCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarSynteninGluK1, GluK2YesPlasma membrane dynamicsHirbec et al., 2003Hirbec H. Francis J.C. Lauri S.E. Braithwaite S.P. Coussen F. Mulle C. Dev K.K. Coutinho V. Meyer G. Isaac J.T.R. et al.Rapid and differential regulation of AMPA and kainate receptors at hippocampal mossy fibre synapses by PICK1 and GRIP.Neuron. 2003; 37: 625-638Abstract Full Text Full Text PDF PubMed Scopus (127) Google ScholarVILIP-1GluK2YesNDCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarVILIP-3GluK2YesNDCoussen et al., 2005Coussen F. Perrais D. Jaskolski F. Sachidhanandam S. Normand E. Bockaert J. Marin P. Mulle C. Co-assembly of two GluR6 kainate receptor splice variants within a functional protein complex.Neuron. 2005; 47: 555-566Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarND, not determined. Open table in a new tab ND, not determined. It was recently demonstrated that the SNARE protein SNAP-25 is a KAR-interacting protein (Selak et al., 2009Selak S. Paternain A.V. Aller M.I. Picó E. Rivera R. Lerma J. A role for SNAP25 in internalization of kainate receptors and synaptic plasticity.Neuron. 2009; 63: 357-371Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). In MF-CA3 synapses, activity-dependent stimulation of PKC intensifies this interaction and triggers the internalization of KARs, leading to a specific long-term depression (LTD) of KAR-mediated synaptic transmission. Interestingly, these results implied that SNAP25, classically regarded as a member of the exocytotic machinery, may be also involved in endocytosis (Selak et al., 2009Selak S. Paternain A.V. Aller M.I. Picó E. Rivera R. Lerma J. A role for SNAP25 in internalization of kainate receptors and synaptic plasticity.Neuron. 2009; 63: 357-371Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). This view has been recently supported by a report defining a role for SNAP25 in clathrin-dependent endocytosis at conventional synapses (Zhang et al., 2013Zhang Z. Wang D. Sun T. Xu J. Chiang H.C. Shin W. Wu L.G. The SNARE proteins SNAP25 and synaptobrevin are involved in endocytosis at hippocampal synapses.J. Neurosci. 2013; 33: 9169-9175Crossref PubMed Scopus (10) Google Scholar). KARs at these synapses may also contain GluK2 subunits and, recently, it was proposed that this mechanism of LTD requires the synergistic SUMOylation of GluK2 subunits, initiated by PKC phosphorylation (Chamberlain et al., 2012Chamberlain S.E.L. González-González I.M. Wilkinson K.A. Konopacki F.A. Kantamneni S. Henley J.M. Mellor J.R. SUMOylation and phosphorylation of GluK2 regulate kainate receptor trafficking and synaptic plasticity.Nat. Neurosci. 2012; 15: 845-852Crossref PubMed Scopus (22) Google Scholar). This new mechanism expands the repertoire of events associated with synaptic plasticity. The possibility of modifying information transfer at this level has been further illustrated by the recent observation that CaMKII-mediated phosphorylation of GluK5 subunits also depresses a KAR-mediated synaptic component at CA3 synapses (Carta et al., 2013Carta M. Opazo P. Veran J. Athané A. Choquet D. Coussen F. Mulle C. CaMKII-dependent phosphorylation of GluK5 mediates plasticity of kainate receptors.EMBO J. 2013; 32: 496-510Crossref PubMed Scopus (6) Google Scholar). A spike timing-dependent plasticity protocol, known to activate CaMKII in a number of synapses and induce AMPAR LTP, induces phosphorylation of GluK5-containing receptors in MF-CA3 synapses, resulting in LTD of the KAR-mediated synaptic component. Rather than involving endocytosis of KARs, this depression is evoked by the lateral diffusion of these receptors upon uncoupling of the PSD-95 scaffolding protein at the postsynaptic density (Carta et al., 2013Carta M. Opazo P. Veran J. Athané A. Choquet D. Coussen F. Mulle C. CaMKII-dependent phosphorylation of GluK5 mediates plasticity of kainate receptors.EMBO J. 2013; 32: 496-510Crossref PubMed Scopus (6) Google Scholar; see also Copits and Swanson, 2013aCopits B.A. Swanson G.T. Lateral thinking: CaMKII uncouples kainate receptors from mossy fibre synapses.EMBO J. 2013; 32: 487-489Crossref PubMed Scopus (1) Google Scholar). Additional proteins that interact and directly modulate the properties of KARs have also been identified. These include proteins such as kainate receptor interacting protein for GluR6 (KRIP6; Laezza et al., 2007Laezza F. Wilding T.J. Sequeira S. Coussen F. Zhang X.Z. Hill-Robinson R. Mulle C. Huettner J.E. Craig A.M. KRIP6: a novel BTB/kelch protein regulating function of kainate receptors.Mol. Cell. Neurosci. 2007; 34: 539-550Crossref PubMed Scopus (25) Google Scholar), a protein that belongs to the BTB/kelch family and that binds to a C-terminal motif distinct to the PDZ binding motif. Coexpression of KRIP6 with GluK2 reduces both the peak current and steady-state desensitization in recombinant systems, as well as that of native KARs. Interestingly, KRIP6 does not affect the surface expression of GluK2 receptors, indicating that the interaction with this protein only affects channel gating. Another BTB/kelch family member, actinfilin, is also thought to interact with GluK2 subunits (Salinas et al., 2006Salinas G.D. Blair L.A.C. Needleman L.A. Gonzales J.D. Chen Y. Li M. Singer J.D. Marshall J. Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway.J. Biol. Chem. 2006; 281: 40164-40173Crossref PubMed Scopus (43) Google Scholar), this protein promoting the degradation of GluK2 receptors by acting as a scaffold to link this subunit to the E3 ubiquitin-ligase complex. In this way, actinfilin regulates the synaptic expression of receptors containing GluK2 (Salinas et al., 2006Salinas G.D. Blair L.A.C. Needleman L.A. Gonzales J.D. Chen Y. Li M. Singer J.D. Marshall J. Actinfilin is a Cul3 substrate adaptor, linking GluR6 kainate receptor subunits to the ubiquitin-proteasome pathway.J. Biol. Chem. 2006; 281: 40164-40173Crossref PubMed Scopus (43) Google Scholar), although more work w
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