G2Cdb::Gene report

Gene id
G00000120
Gene symbol
Homer1 (MGI)
Species
Mus musculus
Description
homer homolog 1 (Drosophila)
Orthologue
G00001369 (Homo sapiens)

Databases (11)

Curated Gene
OTTMUSG00000016339 (Vega mouse gene)
Gene
ENSMUSG00000007617 (Ensembl mouse gene)
26556 (Entrez Gene)
35 (G2Cdb plasticity & disease)
Gene Expression
NM_011982 (Allen Brain Atlas)
g00229 (BGEM)
26556 (Genepaint)
homer1 (gensat)
Literature
604798 (OMIM)
Marker Symbol
MGI:1347345 (MGI)
Protein Sequence
Q9Z2Y3 (UniProt)

Synonyms (2)

  • PSD-Zip45
  • Ves-1

Literature (39)

Pubmed - other

  • Homeostatic scaling requires group I mGluR activation mediated by Homer1a.

    Hu JH, Park JM, Park S, Xiao B, Dehoff MH, Kim S, Hayashi T, Schwarz MK, Huganir RL, Seeburg PH, Linden DJ and Worley PF

    Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

    Homeostatic scaling is a non-Hebbian form of neural plasticity that maintains neuronal excitability and informational content of synaptic arrays in the face of changes of network activity. Here, we demonstrate that homeostatic scaling is dependent on group I metabotropic glutamate receptor activation that is mediated by the immediate early gene Homer1a. Homer1a is transiently upregulated during increases in network activity and evokes agonist-independent signaling of group I mGluRs that scales down the expression of synaptic AMPA receptors. Homer1a effects are dynamic and play a role in the induction of scaling. Similar to mGluR-LTD, Homer1a-dependent scaling involves a reduction of tyrosine phosphorylation of GluA2 (GluR2), but is distinct in that it exploits a unique signaling property of group I mGluR to confer cell-wide, agonist-independent activation of the receptor. These studies reveal an elegant interplay of mechanisms that underlie Hebbian and non-Hebbian plasticity.

    Funded by: NIDA NIH HHS: DA010309, DA011742, R01 DA010309, R01 DA011742, R01 DA011742-13, R37 DA010309, R37 DA010309-16; NIMH NIH HHS: MH084020, P50 MH084020; NINDS NIH HHS: NS036715, R01 NS036715

    Neuron 2010;68;6;1128-42

  • Homer1a-dependent crosstalk between NMDA and metabotropic glutamate receptors in mouse neurons.

    Bertaso F, Roussignol G, Worley P, Bockaert J, Fagni L and Ango F

    Departement of Neurobiology, Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université de Montpellier 1 & 2, Montpellier, France.

    Background: A large number of evidences suggest that group-I metabotropic glutamate receptors (mGluR1a, 1b, 1c, 5a, 5b) can modulate NMDA receptor activity. Interestingly, a physical link exists between these receptors through a Homer-Shank multi-protein scaffold that can be disrupted by the immediate early gene, Homer1a. Whether such a versatile link supports functional crosstalk between the receptors is unknown.

    Here we used biochemical, electrophysiological and molecular biological approaches in cultured mouse cerebellar neurons to investigate this issue. We found that Homer1a or dominant negative Shank3 mutants that disrupt the physical link between the receptors allow inhibition of NMDA current by group-I mGluR agonist. This effect is antagonized by pertussis toxin, but not thapsigargin, suggesting the involvement of a G protein, but not intracellular calcium stores. Also, this effect is voltage-sensitive, being present at negative, but not positive membrane potentials. In the presence of DHPG, an apparent NMDA "tail current" was evoked by large pulse depolarization, only in neurons transfected with Homer1a. Co-immunoprecipitation experiments showed interaction between G-protein betagamma subunits and NMDA receptor in the presence of Homer1a and group-I mGluR agonist.

    Altogether these results suggest a direct inhibition of NMDA receptor-channel by Gbetagamma subunits, following disruption of the Homer-Shank3 complex by the immediate early gene Homer1a. This study provides a new molecular mechanism by which group-I mGluRs could dynamically regulate NMDA receptor function.

    PloS one 2010;5;3;e9755

  • Electroacupuncture inhibits ethanol-induced locomotor sensitization and alters homer1A mRNA expression in mice.

    dos Santos JG, Filev R, Coelho CT, Yamamura Y, Mello LE and Tabosa A

    Department of Physiological Sciences, Faculdade de Ciências Médicas da Santa Casa de São Paulo, São Paulo, Brazil.

    Background: Here we investigated the effects of electroacupuncture over locomotor sensitization induced by ethanol in mice.

    Methods: Adult male Swiss mice were daily injected with ethanol (2 g/kg, i.p.) or saline for 21 days (acquisition phase). After 4 days of withdrawal, all animals were challenged with ethanol (1.4 g/kg, i.p.). The locomotor activity during 30 minutes was accessed just after the ethanol challenge. Electroacupuncture at acquisition, expression, or maintenance phases of locomotor sensitization was provided over ST-36 (Zusanli) or PC-6 (Neiguan) as well as concomitantly over these 2 acupoints. One hour after the challenge with ethanol, the animals were decapitated, the hippocampus, striatum, and prefrontal cortex were dissected, and the expression of homer1A mRNA assessed by PCR.

    Results: Electroacupuncture provided simultaneously over ST-36 and PC-6 (but not to ST-36 or PC-6 alone) inhibited the acquisition, expression, and maintenance of ethanol-induced locomotor sensitization. In addition, electroacupuncture blocked the diminution of homer1A mRNA expression triggered by ethanol in the acquisition (striatum and prefrontal cortex), expression (hippocampus), and in the maintenance (hippocampus and prefrontal cortex) phases.

    Conclusion: Electroacupuncture provided concomitantly over ST-36 and PC-6 prevents the sensitization of the mesocorticolimbic pathway induced by ethanol in mice. In addition, these effects were accompanied by changes in the expression of homer1A. We suggest that electroacupuncture effects over ethanol-induced locomotor sensitization are associated to its ability to modulate homer1A expression and glutamatergic plasticity.

    Alcoholism, clinical and experimental research 2009;33;8;1469-75

  • Input-specific spine entry of soma-derived Vesl-1S protein conforms to synaptic tagging.

    Okada D, Ozawa F and Inokuchi K

    Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya, Machida, Tokyo 194-8511, Japan. dada@mitils.jp

    Late-phase synaptic plasticity depends on the synthesis of new proteins that must function only in the activated synapses. The synaptic tag hypothesis requires input-specific functioning of these proteins after undirected transport. Confirmation of this hypothesis requires specification of a biochemical tagging activity and an example protein that behaves as the hypothesis predicts. We found that in rat neurons, soma-derived Vesl-1S (Homer-1a) protein, a late-phase plasticity-related synaptic protein, prevailed in every dendrite and did not enter spines. N-methyl-d-aspartate receptor activation triggered input-specific spine entry of Vesl-1S proteins, which met many criteria for synaptic tagging. These results suggest that Vesl-1S supports the hypothesis and that the activity-dependent regulation of spine entry functions as a synaptic tag.

    Science (New York, N.Y.) 2009;324;5929;904-9

  • Requirement of the immediate early gene vesl-1S/homer-1a for fear memory formation.

    Inoue N, Nakao H, Migishima R, Hino T, Matsui M, Hayashi F, Nakao K, Manabe T, Aiba A and Inokuchi K

    Mitsubishi Kagaku Institute of Life Sciences, MITILS, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. inouenok@yahoo.co.jp

    Background: The formation of long-term memory (LTM) and the late phase of long-term potentiation (L-LTP) depend on macromolecule synthesis, translation, and transcription in neurons. vesl-1S (VASP/Ena-related gene upregulated during seizure and LTP, also known as homer-1a) is an LTP-induced immediate early gene. The short form of Vesl (Vesl-1S) is an alternatively spliced isoform of the vesl-1 gene, which also encodes the long form of the Vesl protein (Vesl-1L). Vesl-1L is a postsynaptic scaffolding protein that binds to and modulates the metabotropic glutamate receptor 1/5 (mGluR1/5), the IP3 receptor, and the ryanodine receptor. Vesl-1 null mutant mice show abnormal behavior, which includes anxiety- and depression-related behaviors, and an increase in cocaine-induced locomotion; however, the function of the short form of Vesl in behavior is poorly understood because of the lack of short-form-specific knockout mice.

    Results: In this study, we generated short-form-specific gene targeting (KO) mice by knocking in part of vesl-1L/homer-1c cDNA. Homozygous KO mice exhibited normal spine number and morphology. Using the contextual fear conditioning test, we demonstrated that memory acquisition and short-term memory were normal in homozygous KO mice. In contrast, these mice showed impairment in fear memory consolidation. Furthermore, the process from recent to remote memory was affected in homozygous KO mice. Interestingly, reactivation of previously consolidated fear memory attenuated the conditioning-induced freezing response in homozygous KO mice, which suggests that the short form plays a role in fear memory reconsolidation. General activity, emotional performance, and sensitivity to electrofootshock were normal in homozygous KO mice.

    Conclusion: These results indicate that the short form of the Vesl family of proteins plays a role in multiple steps of long-term, but not short-term, fear memory formation.

    Molecular brain 2009;2;7

  • Mice lacking Homer 1 exhibit a skeletal myopathy characterized by abnormal transient receptor potential channel activity.

    Stiber JA, Zhang ZS, Burch J, Eu JP, Zhang S, Truskey GA, Seth M, Yamaguchi N, Meissner G, Shah R, Worley PF, Williams RS and Rosenberg PB

    Department of Medicine, Duke University Medical Center, 4321 Medical Park Drive, Suite 200, Durham, NC 27704, USA.

    Transient receptor potential (TRP) channels are nonselective cation channels, several of which are expressed in striated muscle. Because the scaffolding protein Homer 1 has been implicated in TRP channel regulation, we hypothesized that Homer proteins play a significant role in skeletal muscle function. Mice lacking Homer 1 exhibited a myopathy characterized by decreased muscle fiber cross-sectional area and decreased skeletal muscle force generation. Homer 1 knockout myotubes displayed increased basal current density and spontaneous cation influx. This spontaneous cation influx in Homer 1 knockout myotubes was blocked by reexpression of Homer 1b, but not Homer 1a, and by gene silencing of TRPC1. Moreover, diminished Homer 1 expression in mouse models of Duchenne's muscular dystrophy suggests that loss of Homer 1 scaffolding of TRP channels may contribute to the increased stretch-activated channel activity observed in mdx myofibers. These findings provide direct evidence that Homer 1 functions as an important scaffold for TRP channels and regulates mechanotransduction in skeletal muscle.

    Funded by: Howard Hughes Medical Institute; NHLBI NIH HHS: K08 HL071841, K08 HL077520, R01 HL093470

    Molecular and cellular biology 2008;28;8;2637-47

  • Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate.

    Mackiewicz M, Paigen B, Naidoo N and Pack AI

    Department of Medicine, Center for Sleep and Respiratory Neurobiology, University of Pennsylvania School of Medicine, Translational Research Laboratories, Philadelphia, PA 19104-3403, USA. mirekmm@mail.med.upenn.edu

    Electroencephalographic oscillations in the frequency range of 0.5-4 Hz, characteristic of slow-wave sleep (SWS), are often referred to as the delta oscillation or delta power. Delta power reflects sleep intensity and correlates with the homeostatic response to sleep loss. A published survey of inbred strains of mice demonstrated that the time course of accumulation of delta power varied among inbred strains, and the segregation of the rebound of delta power in BxD recombinant inbred strains identified a genomic region on chromosome 13 referred to as the delta power in SWS (or Dps1). The quantitative trait locus (QTL) contains genes that modify the accumulation of delta power after sleep deprivation. Here, we narrow the QTL using interval-specific haplotype analysis and present a comprehensive annotation of the remaining genes in the Dps1 region with sequence comparisons to identify polymorphisms within the coding and regulatory regions. We established the expression pattern of selected genes located in the Dps1 interval in sleep and wakefulness in B6 and D2 parental strains. Taken together, these steps reduced the number of potential candidate genes that may underlie the accumulation of delta power after sleep deprivation and explain the Dps1 QTL. The strongest candidate gene is Homer1a, which is supported by expression differences between sleep and wakefulness and the SNP polymorphism in the upstream regulatory regions.

    Funded by: NHLBI NIH HHS: HL-60287, HL-66611; NIA NIH HHS: AG-17628

    Physiological genomics 2008;33;1;91-9

  • Homer1a is a core brain molecular correlate of sleep loss.

    Maret S, Dorsaz S, Gurcel L, Pradervand S, Petit B, Pfister C, Hagenbuchle O, O'Hara BF, Franken P and Tafti M

    Center for Integrative Genomics and Lausanne DNA Array Facility, University of Lausanne, Génopode, CH-1015 Lausanne, Switzerland.

    Sleep is regulated by a homeostatic process that determines its need and by a circadian process that determines its timing. By using sleep deprivation and transcriptome profiling in inbred mouse strains, we show that genetic background affects susceptibility to sleep loss at the transcriptional level in a tissue-dependent manner. In the brain, Homer1a expression best reflects the response to sleep loss. Time-course gene expression analysis suggests that 2,032 brain transcripts are under circadian control. However, only 391 remain rhythmic when mice are sleep-deprived at four time points around the clock, suggesting that most diurnal changes in gene transcription are, in fact, sleep-wake-dependent. By generating a transgenic mouse line, we show that in Homer1-expressing cells specifically, apart from Homer1a, three other activity-induced genes (Ptgs2, Jph3, and Nptx2) are overexpressed after sleep loss. All four genes play a role in recovery from glutamate-induced neuronal hyperactivity. The consistent activation of Homer1a suggests a role for sleep in intracellular calcium homeostasis for protecting and recovering from the neuronal activation imposed by wakefulness.

    Funded by: NIMH NIH HHS: MH67752, R01 MH067752

    Proceedings of the National Academy of Sciences of the United States of America 2007;104;50;20090-5

  • Localization and expression of group I metabotropic glutamate receptors in the mouse striatum, globus pallidus, and subthalamic nucleus: regulatory effects of MPTP treatment and constitutive Homer deletion.

    Kuwajima M, Dehoff MH, Furuichi T, Worley PF, Hall RA and Smith Y

    Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

    Group I metabotropic glutamate receptors (mGluRs), mGluR1 and mGluR5, regulate activity in the globus pallidus (GP) and subthalamic nucleus (STN). To test whether the localization of group I mGluRs is altered in parkinsonism, we used immunoelectron microscopy to analyze the subcellular and subsynaptic distribution of mGluR1a and mGluR5 in GP and STN of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Homer1 and Homer2 knock-out mice were used to assess the role of Homer in MPTP-induced redistribution of group I mGluRs. We also examined the effects of MPTP on the expression levels of group I mGluRs and Homer proteins in GP and striatum. MPTP treatment significantly reduced the expression levels of H1a and mGluR1a in striatum but not in GP. Although light microscopy did not reveal noticeable effects of MPTP treatment on the distribution of group I mGluRs and Homer proteins in GP and STN, specific changes in the ultrastructural localization of mGluR1a were found in MPTP-treated normal and Homer knock-out mice. An increase in the expression of presynaptic axonal and terminal mGluR1a labeling and an increased level of mGluR1a immunoreactivity in the postsynaptic specialization of putative GABAergic synapses were among the most significant effects induced by dopamine depletion. However, neither of these changes was found for mGluR5, which, in contrast, displayed complex regulatory alterations in its subsynaptic distribution in response to Homer deletion and MPTP lesion. Thus, nigrostriatal dopaminergic lesion and Homer deletion lead to changes in the trafficking of group I mGluRs in vivo that are specific to receptor subtypes and brain areas.

    Funded by: NCRR NIH HHS: RR00165

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2007;27;23;6249-60

  • Ca2+ signaling in microdomains: Homer1 mediates the interaction between RyR2 and Cav1.2 to regulate excitation-contraction coupling.

    Huang G, Kim JY, Dehoff M, Mizuno Y, Kamm KE, Worley PF, Muallem S and Zeng W

    Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

    Excitation-contraction (E-C) coupling and Ca(2+)-induced Ca(2+) release in smooth and cardiac muscles is mediated by the L-type Ca(2+) channel isoform Ca(v)1.2 and the ryanodine receptor isoform RyR2. Although physical coupling between Ca(v)1.1 and RyR1 in skeletal muscle is well established, it is generally assumed that Ca(v)1.2 and RyR2 do not directly communicate either passively or dynamically during E-C coupling. In the present work, we re-examined this assumption by studying E-C coupling in the detrusor muscle of wild type and Homer1(-/-) mice and by demonstrating a Homer1-mediated dynamic interaction between Ca(v)1.2 and RyR2 using the split green fluorescent protein technique. Deletion of Homer1 in mice (but not of Homer2 or Homer3) resulted in impaired urinary bladder function, which was associated with higher sensitivity of the detrusor muscle to muscarinic stimulation and membrane depolarization. This was not due to an altered expression or function of RyR2 and Ca(v)1.2. Most notably, expression of Ca(v)1.2 and RyR2 tagged with the complementary C- and N-terminal halves of green fluorescent protein and in the presence and absence of Homer1 isoforms revealed that H1a and H1b/c reciprocally modulates a dynamic interaction between Ca(v)1.2 and RyR2 to regulate the intensity of Ca(2+)-induced Ca(2+) release and its dependence on membrane depolarization. These findings define the molecular basis of a "two-state" model of E-C coupling by Ca(v)1.2 and RyR2. In one state, Ca(v)1.2 couples to RyR2 by H1b/c, which results in reduced responsiveness to membrane depolarization and in the other state H1a uncouples Ca(v)1.2 and RyR2 to enhance responsiveness to membrane depolarization. These findings reveal an unexpected and novel mode of interaction and communication between Ca(v)1.2 and RyR2 with important implications for the regulation of smooth and possibly cardiac muscle E-C coupling.

    Funded by: NIDA NIH HHS: DA00266, DA10309; NIDCR NIH HHS: DE12309; NIDDK NIH HHS: DK38938; NIMH NIH HHS: MH068830

    The Journal of biological chemistry 2007;282;19;14283-90

  • The fundamental properties of Homer 1 in association with cardiac ryanodine receptor in mouse heart.

    Kawaguchi S, Shoji S, Sunamori M, Furuichi T and Kawano S

    Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama, Japan. skawtsrg@tmd.ac.jp

    Background: Homer, known as a scaffolding protein that regulates postsynapse signaling in neurons, has been poorly explored in cardiac research. We show the fundamental properties of Homer 1 in mouse heart in association with cardiac ryanodine receptor (RyR), a binding protein of Homer 1.

    Immunohistochemistry of adult mouse heart with Homer 1 antibody showed striated staining on Z-bands both in atria and ventricles. The interactions between Homer 1 and RyR were confirmed by co-immunoprecipitation assays. Immunostaining of adult isolated cardiomyocytes showed partial co-localization of both proteins. In neonatal primary cultures, targeting of Homer 1 preceded that of RyR in their Z-band arrangement.

    Conclusions: Homer 1 binds to RyR in adult mouse heart and precedes RyR in Z-band arrangement in the early postnatal period.

    Journal of medical and dental sciences 2007;54;1;103-8

  • Alternative poly(A) site-selection regulates the production of alternatively spliced vesl-1/homer1 isoforms that encode postsynaptic scaffolding proteins.

    Niibori Y, Hayashi F, Hirai K, Matsui M and Inokuchi K

    Mitsubishi Kagaku Institute of Life Sciences (MITILS), 11 Minamiooya, Machida, Tokyo, Japan.

    The vesl-1/homer1 gene encodes a scaffold protein that interacts with several receptors to modulate synaptic functions. The gene also encodes two shorter forms that counteract the functions of the long form of Vesl. Expression of the shorter forms is driven by neural activities such as long-term potentiation. Here we analyzed the mechanism regulating vesl-1 alternative splicing. Each functional poly(A) site was in a different part of the 3'-terminal exon, with promoter-proximal and promoter-distal sites at the end of exons corresponding to the short and long form Vesl-1, respectively. 3'-End-processing at proximal poly(A) site, specifically at the vesl-1M poly(A) site, was enhanced by extracellular stimuli, thereby switching transcription termination from promoter-distal to -proximal poly(A) site. This switch was not specifically coupled to the vesl-1 promoter and was independent of de novo protein synthesis. Analysis of transcripts from mini-genes that mimic the structure of endogenous vesl-1 revealed that the vesl-1M poly(A) region plays a crucial role in switching to the alternative pre-mRNA splicing that is triggered by extracellular stimuli. Therefore, a 3'-end-processing event regulates the neural activity-dependent alternative splicing of vesl-1. This is the first report of a gene in which alternative poly(A) site-selection regulates alternative splicing in a protein synthesis-independent manner.

    Neuroscience research 2007;57;3;399-410

  • Complex, multimodal behavioral profile of the Homer1 knockout mouse.

    Jaubert PJ, Golub MS, Lo YY, Germann SL, Dehoff MH, Worley PF, Kang SH, Schwarz MK, Seeburg PH and Berman RF

    Children's Center for Environmental Health & Department of Neurological Surgery, University of California Davis, CA 95616, USA.

    Proteins of the Homer1 immediate early gene family have been associated with synaptogenesis and synaptic plasticity suggesting broad behavioral consequences of loss of function. This study examined the behavior of male Homer1 knockout (KO) mice compared with wild-type (WT) and heterozygous mice using a battery of 10 behavioral tests probing sensory, motor, social, emotional and learning/memory functions. KO mice showed mild somatic growth retardation, poor motor coordination, enhanced sensory reactivity and learning deficits. Heterozygous mice showed increased aggression in social interactions with conspecifics. The distribution of mGluR5 and N-methyl-D-aspartate receptors (NMDA) receptors appeared to be unaltered in the hippocampus (HIP) of Homer1 KO mice. The results indicate an extensive range of disrupted behaviors that should contribute to the understanding of the Homer1 gene in brain development and behavior.

    Funded by: NIEHS NIH HHS: 1 P01 ES11269

    Genes, brain, and behavior 2007;6;2;141-54

  • Transgenic mouse proteomics identifies new 14-3-3-associated proteins involved in cytoskeletal rearrangements and cell signaling.

    Angrand PO, Segura I, Völkel P, Ghidelli S, Terry R, Brajenovic M, Vintersten K, Klein R, Superti-Furga G, Drewes G, Kuster B, Bouwmeester T and Acker-Palmer A

    Cellzome AG and the European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany. pierre-olivier.angrand@ibl.fr

    Identification of protein-protein interactions is crucial for unraveling cellular processes and biochemical mechanisms of signal transduction. Here we describe, for the first time, the application of the tandem affinity purification (TAP) and LC-MS method to the characterization of protein complexes from transgenic mice. The TAP strategy developed in transgenic mice allows the emplacement of complexes in their physiological environment in contact with proteins that might only be specifically expressed in certain tissues while simultaneously ensuring the right stoichiometry of the TAP protein versus their binding partners and represents a novelty in proteomics approaches used so far. Mouse lines expressing TAP-tagged 14-3-3zeta protein were generated, and protein interactions were determined. 14-3-3 proteins are general regulators of cell signaling and represent up to 1% of the total brain protein. This study allowed the identification of almost 40 novel 14-3-3zeta-binding proteins. Biochemical and functional characterization of some of these interactions revealed new mechanisms of action of 14-3-3zeta in several signaling pathways, such as glutamate receptor signaling via binding to homer homolog 3 (Homer 3) and in cytoskeletal rearrangements and spine morphogenesis by binding and regulating the activity of the signaling complex formed by G protein-coupled receptor kinase-interactor 1 (GIT1) and p21-activated kinase-interacting exchange factor beta (betaPIX).

    Molecular & cellular proteomics : MCP 2006;5;12;2211-27

  • Differential control of postsynaptic density scaffolds via actin-dependent and -independent mechanisms.

    Kuriu T, Inoue A, Bito H, Sobue K and Okabe S

    Department of Cell Biology, School of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan.

    Organization and dynamic remodeling of postsynaptic density (PSD) are thought to be critical in postsynaptic signal transduction, but the underlying molecular mechanisms are not well understood. We show here that four major scaffolding molecules, PSD-95, GKAP, Shank, and PSD-Zip45, show distinct instability in total molecular content per synapse. Fluorescence recovery after photobleaching also confirmed their distinct turnover rates. Among the PSD molecules examined, PSD-95 was most stable, but its elimination did not influence the dynamics of its direct binding partner GKAP. Multiple interactions of scaffolding molecules with the actin cytoskeleton have suggested their importance in both maintenance and remodeling of the PSD. Indeed, acute pharmacological disruption of F-actin rapidly eliminated the dynamic fraction of GKAP, Shank, and PSD-Zip45, without changing synaptic localization of PSD-95. GKAP content in synapses increased after pharmacological enhancement of neuronal activity, whereas Shank and PSD-Zip45 content showed reduction. Inhibition of F-actin dynamics prevented activity-dependent redistribution of all three scaffolds. We also assessed involvement of glutamate receptors in the regulation of PSD dynamics. Genetic manipulations eliminating either NMDA receptors or metabotropic glutamate receptors did not primarily influence mobility of their binding scaffolds. These results collectively indicate a critical role of filamentous actin in determining the extent of dynamic reorganization in PSD molecular composition.

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2006;26;29;7693-706

  • Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain.

    Tappe A, Klugmann M, Luo C, Hirlinger D, Agarwal N, Benrath J, Ehrengruber MU, During MJ and Kuner R

    Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.

    Glutamatergic signaling and intracellular calcium mobilization in the spinal cord are crucial for the development of nociceptive plasticity, which is associated with chronic pathological pain. Long-form Homer proteins anchor glutamatergic receptors to sources of calcium influx and release at synapses, which is antagonized by the short, activity-dependent splice variant Homer1a. We show here that Homer1a operates in a negative feedback loop to regulate the excitability of the pain pathway in an activity-dependent manner. Homer1a is rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor-dependent manner. Homer1a strongly attenuates calcium mobilization as well as MAP kinase activation induced by glutamate receptors and reduces synaptic contacts on spinal cord neurons that process pain inputs. Preventing activity-induced upregulation of Homer1a using shRNAs in mice in vivo exacerbates inflammatory pain. Thus, activity-dependent uncoupling of glutamate receptors from intracellular signaling mediators is a novel, endogenous physiological mechanism for counteracting sensitization at the first, crucial synapse in the pain pathway. Furthermore, we observed that targeted gene transfer of Homer1a to specific spinal segments in vivo reduces inflammatory hyperalgesia. Thus, Homer1 function is crucially involved in pain plasticity and constitutes a promising therapeutic target for the treatment of chronic inflammatory pain.

    Nature medicine 2006;12;6;677-81

  • BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system.

    Magdaleno S, Jensen P, Brumwell CL, Seal A, Lehman K, Asbury A, Cheung T, Cornelius T, Batten DM, Eden C, Norland SM, Rice DS, Dosooye N, Shakya S, Mehta P and Curran T

    Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States.

    Funded by: NINDS NIH HHS: 5R37NS036558, N01-NS-0-2331, R37 NS036558

    PLoS biology 2006;4;4;e86

  • Regulation of motor performance and striatal function by synaptic scaffolding proteins of the Homer1 family.

    Tappe A and Kuner R

    Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg 69120, Germany.

    Intracellular calcium mobilization and signaling mechanisms triggered by activation of synaptic glutamate receptors in the striatum are important modulators of neurotransmission in striatal circuits. However, the expression and functions of scaffolding proteins anchoring glutamate receptors at striatal synapses have not been addressed so far. The long-form Homer1 proteins, Homer1b/c, assemble group I metabotropic glutamate receptors (mGluR1/5) in large macromolecular complexes with sources of calcium influx and release at synapses as well as with components of the NMDA receptor complex at the neuronal cell membrane. Homer1a, the short, activity-dependent splice variant of Homer1b/c, lacks the ability of linking mGluR1/5 to synaptic proteins and functions as an endogenous negative modulator of the mGluR1/5 inositol 1,4,5-trisphosphate receptor signaling complex. We have generated transgenic mice, which overexpress Homer1a in striatal medium spiny neurons either homogenously throughout the extrastriosomal matrix (Homer1a-matrix line) or predominantly in striosomal patches (Homer1a-striosome line). Homer1a-expressing mice demonstrated normal development of striatal structure and afferent-efferent connectivity. However, motor performance in behavioral tasks and striatal responses to the psychomotor stimulant amphetamine were significantly altered in the Homer1a-striosome line. Thus, glutamate receptor scaffolding proteins of the Homer1 family critically regulate the functions of striatal medium spiny neurons in complex motor tasks and its modulation by psychomotor stimulant drugs.

    Proceedings of the National Academy of Sciences of the United States of America 2006;103;3;774-9

  • Distinct roles for different Homer1 isoforms in behaviors and associated prefrontal cortex function.

    Lominac KD, Oleson EB, Pava M, Klugmann M, Schwarz MK, Seeburg PH, During MJ, Worley PF, Kalivas PW and Szumlinski KK

    Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.

    Homer1 mutant mice exhibit behavioral and neurochemical abnormalities that are consistent with an animal model of schizophrenia. Because the Homer1 gene encodes both immediate early gene (IEG) and constitutively expressed (CC) gene products, we used the local infusion of adeno-associated viral vectors carrying different Homer1 transcriptional variants into the prefrontal cortex (PFC) to distinguish between the roles for IEG and CC Homer1 isoforms in the "schizophrenia-like" phenotype of Homer1 mutant mice. PFC overexpression of the IEG Homer1 isoform Homer1a reversed the genotypic differences in behavioral adaptation to repeated stress, whereas overexpression of the constitutively expressed Homer1 isoform Homer1c reversed the genotypic differences in sensorimotor and cognitive processing, as well as cocaine behavioral sensitivity. Homer1a overexpression did not influence PFC basal glutamate content but blunted the glutamate response to cocaine in wild-type mice. In contrast, Homer1c overexpression reversed the genotypic difference in PFC basal glutamate content and enhanced cocaine-induced elevations in glutamate. These data demonstrate active and distinct roles for Homer1a and Homer1c isoforms in the PFC in the mediation of behavior, in the maintenance of basal extracellular glutamate, and in the regulation of PFC glutamate release relevant to schizophrenia and stimulant abuse comorbidity.

    Funded by: NIDA NIH HHS: DA-03906, DA-10307, DA-11742, DA-14185; NIMH NIH HHS: MH-40817

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2005;25;50;11586-94

  • Homer modulates NFAT-dependent signaling during muscle differentiation.

    Stiber JA, Tabatabaei N, Hawkins AF, Hawke T, Worley PF, Williams RS and Rosenberg P

    Department of Medicine, Duke University, 4321 Medical Park Drive, Suite 200, Durham, NC 27704, USA.

    While changes in intracellular calcium are well known to influence muscle contraction through excitation contraction coupling, little is understood of the calcium signaling events regulating gene expression through the calcineurin/NFAT pathway in muscle. Here, we demonstrate that Ca(+2) released via the inositol trisphosphate receptor (IP3R) increases nuclear entry of NFAT in undifferentiated skeletal myoblasts, but the IP3R Ca(+2) pool in differentiated myotubes promotes nuclear exit of NFAT despite a comparable quantitative change in [Ca(+2)]i. In contrast, Ca(+2) released via ryanodine receptors (RYR) increases NFAT nuclear entry in myotubes. The scaffolding protein Homer, known to interact with both IP3R and RYR, is expressed as part of the myogenic differentiation program and enhances NFAT-dependent signaling by increasing RYR Ca(+2) release. These results demonstrate that differentiated skeletal myotubes employ discrete pools of intracellular calcium to restrain (IP3R pool) or activate (RYR pool) NFAT-dependent signaling, in a manner distinct from undifferentiated myoblasts. The selective expression of Homer proteins contributes to these differentiation-dependent features of calcium signaling.

    Funded by: NHLBI NIH HHS: K08 HL071841, K08 HL077520; NIAMS NIH HHS: R01-AR40849

    Developmental biology 2005;287;2;213-24

  • Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophrenia.

    Szumlinski KK, Lominac KD, Kleschen MJ, Oleson EB, Dehoff MH, Schwarz MK, Schwartz MK, Seeburg PH, Seeberg PH, Worley PF and Kalivas PW

    Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC, USA. szumlink@musc.edu

    Homer proteins are involved in the functional assembly of postsynaptic density proteins at glutamatergic synapses and are implicated in learning, memory and drug addiction. Here, we report that Homer1-knockout (Homer1-KO) mice exhibit behavioral and neurochemical abnormalities that are consistent with the animal models of schizophrenia. Relative to wild-type mice, Homer1-KO mice exhibited deficits in radial arm maze performance, impaired prepulse inhibition, enhanced 'behavioral despair', increased anxiety in a novel objects test, enhanced reactivity to novel environments, decreased instrumental responding for sucrose and enhanced MK-801- and methamphetamine-stimulated motor behavior. No-net-flux in vivo microdialysis revealed a decrease in extracellular glutamate content in the nucleus accumbens and an increase in the prefrontal cortex. Moreover, in Homer1-KO mice, cocaine did not stimulate a rise in frontal cortex extracellular glutamate levels, suggesting hypofrontality. These behavioral and neurochemical data derived from Homer1 mutant mice are consistent with the recent association of schizophrenia with a single-nucleotide polymorphism in the Homer1 gene and suggest that the regulation of extracellular levels of glutamate within limbo-corticostriatal structures by Homer1 gene products may be involved in the pathogenesis of this neuropsychiatric disorder.

    Funded by: NIDA NIH HHS: DA-11742, DA-14185; NIMH NIH HHS: MH-40817

    Genes, brain, and behavior 2005;4;5;273-88

  • Signaling complex formation of phospholipase Cbeta4 with metabotropic glutamate receptor type 1alpha and 1,4,5-trisphosphate receptor at the perisynapse and endoplasmic reticulum in the mouse brain.

    Nakamura M, Sato K, Fukaya M, Araishi K, Aiba A, Kano M and Watanabe M

    Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan.

    Upon activation of cell surface receptors coupled to the Gq subclass of G proteins, phospholipase C (PLC) beta hydrolyses membrane phospholipid to yield a pair of second messengers, inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol. PLCbeta4 has been characterized as the isoform enriched in cerebellar Purkinje cells (PCs) and the retina and involved in motor and visual functions. Here we examined cellular and subcellular distributions of PLCbeta4 in adult mouse brains. Immunohistochemistry showed that high levels of PLCbeta4 were detected in the somatodendritic domain of neuronal populations expressing the metabotropic glutamate receptor (mGluR) type 1alpha, including olfactory periglomerular cells, neurons in the bed nucleus anterior commissure, thalamus, substantia nigra, inferior olive, and unipolar brush cells and PCs in the cerebellum. Low to moderate levels were detected in many other mGluR1alpha-positive neurons and in a few mGluR1alpha-negative neurons. In PCs, immunogold electron microscopy localized PLCbeta4 to the perisynapse, at which mGluR1alpha is concentrated, and to the smooth endoplasmic reticulum in dendrites and spines, an intracellular Ca2+ store gated by IP3 receptors. In the cerebellum, immunoblot demonstrated its concentrated distribution in the post-synaptic density and microsomal fractions, where mGluR1alpha and type 1 IP3 receptor were also greatly enriched. Furthermore, PLCbeta4 formed coimmunoprecipitable complexes with mGluR1alpha, type 1 IP3 receptor and Homer 1. These results suggest that PLCbeta4 is preferentially localized in the perisynapse and smooth endoplasmic reticulum as a component of the physically linked phosphoinositide signaling complex. This close molecular relationship might provide PLCbeta4 with a high-fidelity effector function to mediate various neuronal responses under physiological and pathophysiological conditions.

    The European journal of neuroscience 2004;20;11;2929-44

  • Homer proteins regulate sensitivity to cocaine.

    Szumlinski KK, Dehoff MH, Kang SH, Frys KA, Lominac KD, Klugmann M, Rohrer J, Griffin W, Toda S, Champtiaux NP, Berry T, Tu JC, Shealy SE, During MJ, Middaugh LD, Worley PF and Kalivas PW

    Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, SC 29425, USA. szumlink@musc.edu

    Drug addiction involves complex interactions between pharmacology and learning in genetically susceptible individuals. Members of the Homer gene family are regulated by acute and chronic cocaine administration. Here, we report that deletion of Homer1 or Homer2 in mice caused the same increase in sensitivity to cocaine-induced locomotion, conditioned reward, and augmented extracellular glutamate in nucleus accumbens as that elicited by withdrawal from repeated cocaine administration. Moreover, adeno-associated virus-mediated restoration of Homer2 in the accumbens of Homer2 KO mice reversed the cocaine-sensitized phenotype. Further analysis of Homer2 KO mice revealed extensive additional behavioral and neurochemical similarities to cocaine-sensitized animals, including accelerated acquisition of cocaine self-administration and altered regulation of glutamate by metabotropic glutamate receptors and cystine/glutamate exchange. These data show that Homer deletion mimics the behavioral and neurochemical phenotype produced by repeated cocaine administration and implicate Homer in regulating addiction to cocaine.

    Funded by: NIDA NIH HHS: DA-03906, DA-10309, DA-11742, DA-14185, DA-14185-01; NIMH NIH HHS: KO2-MH01152, MH-40817

    Neuron 2004;43;3;401-13

  • Differential expression of Homer family proteins in the developing mouse brain.

    Shiraishi Y, Mizutani A, Yuasa S, Mikoshiba K and Furuichi T

    Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.

    Homer acts as a postsynaptic adaptor protein that links multiple targets, such as proteins involved in glutamate receptor signaling. We report the differential expression of the long form of Homer proteins produced from three distinctive genes during postnatal development of the mouse brain. Homer 1b/c and Cupidin/Homer 2a/b are widespread throughout the developing brain and are down-regulated in hindbrain-origin regions, such as the cerebellum, pons, and medulla oblongata. In contrast, Homer 3a/b is restricted to the cerebellum, hippocampus, and neonatal olfactory bulb. In the cerebellum, Homer 1b/c and Cupidin/Homer 2a/b predominate in the postsynapses of developing granule cells, whereas Homer 3a/b is concentrated in the dendritic spines of Purkinje cells and their axons. The down-regulation of Homer 1b/c and Cupidin/Homer 2a/b is in marked contrast to the up-regulation of Homer 3a/b between the first and the second postnatal weeks. In the hippocampus, Homer 1b/c and Cupidin/Homer 2a/b are largely located in the CA1 region and the CA1-CA2 region, respectively, whereas Homer 3a/b is largely distributed in the CA2-CA3 region and peaks around the third postnatal week. In hippocampal cell cultures, Homer 1b/c and Cupidin/Homer 2a/b are expressed in inhibitory and excitatory neurons, whereas Homer 3a/b is largely expressed in excitatory neurons but not in inhibitory neurons. In the developing olfactory bulb, Homer 1b/c and Cupidin/Homer 2a/b are up-regulated in the granular, external plexiform, and glomerular layers, whereas Homer 3a/b drastically decreases in these regions within the first postnatal week. Cupidin/Homer 2a/b is also expressed in olfactory sensory neurons within a distinct olfactory epithelial zone and is then widely distributed to both the axons in the olfactory nerve layer and the cilia in the olfactory epithelium. These results demonstrate that Homer family members have distinct regional, cellular, and subcellular distributions in time and space during postnatal brain development.

    The Journal of comparative neurology 2004;473;4;582-99

  • Homer protein increases activation of Ca2+ sparks in permeabilized skeletal muscle.

    Ward CW, Feng W, Tu J, Pessah IN, Worley PK and Schneider MF

    Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    Members of the Homer family of proteins are known to form multimeric complexes capable of cross-linking plasma membrane channels (e.g. metabotropic glutamate receptor) and intracellular Ca2+ release channels (e.g. inositol trisphosphate receptor) in neurons, which potentiates Ca2+ release. Recent work has demonstrated direct interaction of Homer proteins with type 1 and type 2 ryanodine receptor (RyR) isoforms. Moreover, Homer proteins have been shown to modulate RyR-dependent Ca2+ release in isolated channels as well as in whole cell preparations. We now show that long and short forms of Homer H1 (H1c and H1-EVH1) are potent activators of Ca2+ release via RyR in skeletal muscle fibers (e.g. Ca2+ sparks) and potent modulators of ryanodine binding to membranes enriched with RyR, with H1c being significantly more potent than H1-EVH1. Homer did not significantly alter the spatio-temporal properties of the sparks, demonstrating that Homer increases the rate of opening of RyRs, with no change in the overall RyR channel open time and amount of Ca2+ released during a spark. No changes in Ca2+ spark frequency or properties were observed using a full-length H1c with mutation in the EVH1 binding domain (H1c-G89N). One novel finding with each Homer agonist (H1c and H1-EVH1) was that in combination their actions on [3H]ryanodine binding was additive, an effect also observed for these Homer agonists in the Ca2+ spark studies. Finally, in Ca2+ spark studies, excess H1c-G89N prevented the effects of H1c in a dominant negative manner. Taken together our results suggest that the EVH1 domain is critical for the agonist behavior on Ca2+ sparks and ryanodine binding, and that the coiled-coil domain, present in long but not short form Homer, confers an increase in agonist potential apparently through the multimeric association of Homer ligand.

    The Journal of biological chemistry 2004;279;7;5781-7

  • GenePaint.org: an atlas of gene expression patterns in the mouse embryo.

    Visel A, Thaller C and Eichele G

    Max Planck Institute of Experimental Endocrinology, Feodor-Lynen-Strasse 7, D-30625 Hannover, Germany.

    High-throughput instruments were recently developed to determine gene expression patterns on tissue sections by RNA in situ hybridization. The resulting images of gene expression patterns, chiefly of E14.5 mouse embryos, are accessible to the public at http://www.genepaint.org. This relational database is searchable for gene identifiers and RNA probe sequences. Moreover, patterns and intensity of expression in approximately 100 different embryonic tissues are annotated and can be searched using a standardized catalog of anatomical structures. A virtual microscope tool, the Zoom Image Server, was implemented in GenePaint.org and permits interactive zooming and panning across approximately 15,000 high-resolution images.

    Nucleic acids research 2004;32;Database issue;D552-6

  • Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

    Zambrowicz BP, Abuin A, Ramirez-Solis R, Richter LJ, Piggott J, BeltrandelRio H, Buxton EC, Edwards J, Finch RA, Friddle CJ, Gupta A, Hansen G, Hu Y, Huang W, Jaing C, Key BW, Kipp P, Kohlhauff B, Ma ZQ, Markesich D, Payne R, Potter DG, Qian N, Shaw J, Schrick J, Shi ZZ, Sparks MJ, Van Sligtenhorst I, Vogel P, Walke W, Xu N, Zhu Q, Person C and Sands AT

    Lexicon Genetics, 8800 Technology Forest Place, The Woodlands, TX 77381, USA. brian@lexgen.com

    The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.

    Proceedings of the National Academy of Sciences of the United States of America 2003;100;24;14109-14

  • Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors.

    Yuan JP, Kiselyov K, Shin DM, Chen J, Shcheynikov N, Kang SH, Dehoff MH, Schwarz MK, Seeburg PH, Muallem S and Worley PF

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

    Receptor signaling at the plasma membrane often releases calcium from intracellular stores. For example, inositol triphosphate (IP3) produced by receptor-coupled phospholipase C activates an intracellular store calcium channel, the IP(3)R. Conversely, stores can induce extracellular calcium to enter the cell through plasma membrane channels, too. How this "reverse" coupling works was unclear, but store IP(3)Rs were proposed to bind and regulate plasma membrane TRP cation channels. Here, we demonstrate that the adaptor protein, termed Homer, facilitates a physical association between TRPC1 and the IP(3)R that is required for the TRP channel to respond to signals. The TRPC1-Homer-IP(3)R complex is dynamic and its disassembly parallels TRPC1 channel activation. Homer's action depends on its ability to crosslink and is blocked by the dominant-negative immediate early gene form, H1a. Since H1a is transcriptionally regulated by cellular activity, this mechanism can affect both short and long-term regulation of TRPC1 function.

    Cell 2003;114;6;777-89

  • Effects of coexpression with Homer isoforms on the function of metabotropic glutamate receptor 1alpha.

    Abe H, Misaka T, Tateyama M and Kubo Y

    Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Graduate School and Faculty of Medicine, Bunkyo, Tokyo, Japan, 113-8519.

    We previously showed that the metabotropic glutamate receptor 1alpha (mGluR1alpha) has a sensitivity to extracellular polyvalent cations such as Ca(2+) and Gd(3+) as well as glutamate. Here we show that mGluR1alpha-mediated responses to these ligands are modulated by the scaffold protein Homer. When HEK293 cells were transiently cotransfected with Homer 1c and mGluR1alpha, the maximum rate of rise and amplitude of glutamate-evoked [Ca(2+)](i) transients were increased and there was a rightward shift in the concentration-response relationship. The response of mGluR1alpha to abrupt increases in [Gd(3+)](o) was characteristic in that the concentration-response relationship was bell-shaped and Homer 1c broadened the effective range at both low and high concentrations. The effects of Homer 1a, which lacks clustering effect, differed qualitatively from those of Homer 1c. The effects of both Homer 1c and 1a on mGluR1alpha were decreased significantly in mGluR1alpha P1147E mutant which lacks the affinity to Homer, showing that the effects were mediated by binding to mGluR1alpha. Taken together, the binding of Homer 1c to mGluR1alpha was shown to cause not only an efficient link to Ca(2+)-store and a decrease in the surface expression, but also qualitative changes of the ligand-sensing function in a ligand type-specific manner.

    Molecular and cellular neurosciences 2003;23;2;157-68

  • Long-term potentiation of mGluR1 activity by depolarization-induced Homer1a in mouse cerebellar Purkinje neurons.

    Minami I, Kengaku M, Smitt PS, Shigemoto R and Hirano T

    Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.

    Metabotropic glutamate receptor 1 (mGluR1) plays a crucial role in synaptic plasticity and motor learning in the cerebellum. We have studied activity-dependent changes in mGluR1 function in mouse cultured Purkinje neurons. Depolarizing stimulation potentiated Ca2+ and current responses to an mGluR1 agonist for several hours in the cultured Purkinje neurons. It also blocked internalization of mGluR1 and increased the number of mGluR1s on the cell membrane. We found that depolarization simultaneously increased transcription of Homer1a in Purkinje neurons. Homer1a inhibited internalization and increased cell-surface expression of mGluR1 when coexpressed in human embryonic kidney (HEK)-293 cells. Depolarization-induced Homer1a expression in Purkinje neurons was blocked by a mitogen-activated protein kinase (MAPK) inhibitor. Changes in internalization and mGluR1-mediated Ca2+ response were also blocked by inhibition of MAPK activity, suggesting that localization and activity of mGluR1 were regulated in the same signalling pathway as Homer1a expression. It is thus suggested that depolarization of the Purkinje neuron leads to the increment in mGluR1 responsiveness through MAPK activity and induction of Homer1a expression, which increases active mGluR1 on the cell surface by blocking internalization of mGluR1.

    The European journal of neuroscience 2003;17;5;1023-32

  • Kindling-induced overexpression of Homer 1A and its functional implications for epileptogenesis.

    Potschka H, Krupp E, Ebert U, Gümbel C, Leichtlein C, Lorch B, Pickert A, Kramps S, Young K, Grüne U, Keller A, Welschof M, Vogt G, Xiao B, Worley PF, Löscher W and Hiemisch H

    Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.

    Despite an extensive research on the molecular basis of epilepsy, the essential players in the epileptogenic process leading to epilepsy are not known. Gene expression analysis is one strategy to enhance our understanding of the genes contributing to the functional neuronal changes underlying epileptogenesis. In the present study, we used the novel MPSS (massively parallel signature sequencing) method for analysis of gene expression in the rat kindling model of temporal lobe epilepsy. Kindling by repeated electrical stimulation of the amygdala resulted in the differential expression of 264 genes in the hippocampus compared to sham controls. The most strongly induced gene was Homer 1A, an immediate early gene involved in the modulation of glutamate receptor function. The overexpression of Homer 1A in the hippocampus of kindled rats was confirmed by RT-PCR. In order to evaluate the functional implications of Homer 1A overexpression for kindling, we used transgenic mice that permanently overexpress Homer 1A. Immunohistochemical characterization of these mice showed a marked Homer 1A overexpression in glutamatergic neurons of the hippocampus. Kindling of Homer 1A overexpressing mice resulted in a retardation of seizure generalization compared to wild-type controls. The data demonstrate that kindling-induced epileptogenesis leads to a striking overexpression of Homer 1A in the hippocampus, which may represent an intrinsic antiepileptogenic and anticonvulsant mechanism in the course of epileptogenesis that counteracts progression of the disease.

    Funded by: NIDA NIH HHS: R01 DA11742; NIMH NIH HHS: MH01152

    The European journal of neuroscience 2002;16;11;2157-65

  • Homer proteins and InsP(3) receptors co-localise in the longitudinal sarcoplasmic reticulum of skeletal muscle fibres.

    Salanova M, Priori G, Barone V, Intravaia E, Flucher B, Ciruela F, McIlhinney RA, Parys JB, Mikoshiba K and Sorrentino V

    Department of Neuroscience, University of Siena, Siena, Italy.

    Striated muscle represents one of the best models for studies on Ca(2+) signalling. However, although much is known on the localisation and molecular interactions of the ryanodine receptors (RyRs), far less is known on the localisation and on the molecular interactions of the inositol trisphosphate receptors (InsP(3)Rs) in striated muscle cells. Recently, members of the Homer protein family have been shown to cluster type 1 metabotropic glutamate receptors (mGluR1) in the plasma membrane and to interact with InsP(3)R in the endoplasmic reticulum of neurons. Thus, these scaffolding proteins are good candidates for organising plasma membrane receptors and intracellular effector proteins in signalosomes involved in intracellular Ca(2+) signalling. Homer proteins are also expressed in skeletal muscle, and the type 1 ryanodine receptor (RyR1) contains a specific Homer-binding motif. We report here on the relative sub-cellular localisation of InsP(3)Rs and Homer proteins in skeletal muscle cells with respect to the localisation of RyRs. Immunofluorescence analysis showed that both Homer and InsP(3)R proteins present a staining pattern indicative of a localisation at the Z-line, clearly distinct from that of RyR1. Consistent herewith, in sub-cellular fractionation experiments, Homer proteins and InsP(3)R were both found in the fractions enriched in longitudinal sarcoplasmic reticulum (LSR) but not in fractions of terminal cisternae that are enriched in RyRs. Thus, in skeletal muscle, Homer proteins may play a role in the organisation of a second Ca(2+) signalling compartment containing the InsP(3)R, but are apparently not involved in the organisation of RyRs at triads.

    Funded by: Telethon: 1151

    Cell calcium 2002;32;4;193-200

  • An N-terminal sequence specific for a novel Homer1 isoform controls trafficking of group I metabotropic glutamate receptor in mammalian cells.

    Saito H, Kimura M, Inanobe A, Ohe T and Kurachi Y

    Department of Pharmacology II, Graduate School of Medicine, Osaka University, Suita, Yamada-oka 2-2, Osaka 565-0871, Japan.

    Homer proteins bind to a proline-rich region of the group I metabotropic glutamate receptors (mGluRs) and control their expression and localization at the excitatory postsynaptic density. We isolated a novel isoform of Homer1, Homer1d, from a mouse heart cDNA library. Its N-terminal end of 18 amino acids was unique among Homer1 variants (Homer1a-d), while the remainder of Homer1d was identical to that of Homer1b. To clarify the function of its N-terminus, we expressed Homer1b and 1d in the presence and absence of mGluR5b in HEK293T cells. When expressed alone, both Homer proteins were distributed diffusely in the cytoplasm and mGluR5b was on the plasma membrane (PM). When co-expressed, Homer1d and mGluR5b were co-localized on the PM, while Homer1b and mGluR5b were retained in the endoplasmic reticulum (ER). Both Homer proteins bound to mGluR5b in vitro. Therefore, the N-terminal portion of Homer1d may facilitate trafficking of Homer1-mGluR5 complex from the ER to the PM.

    Biochemical and biophysical research communications 2002;296;3;523-9

  • Synaptic activity-induced conversion of intronic to exonic sequence in Homer 1 immediate early gene expression.

    Bottai D, Guzowski JF, Schwarz MK, Kang SH, Xiao B, Lanahan A, Worley PF and Seeburg PH

    Department of Molecular Neurobiology, Max-Planck Institute for Medical Research, 69120 Heidelberg, Germany.

    Three Homer genes regulate the activity of metabotropic glutamate receptors mGluR1a and mGluR5 and their coupling to releasable intracellular Ca2+ pools and ion channels. Only the Homer 1 gene evolved bimodal expression of constitutive (Homer 1b and c) and immediate early gene (IEG) products (Homer 1a and Ania 3). The IEG forms compete functionally with the constitutive Homer proteins. The complex expression of the Homer 1 gene, unique for IEGs, focused our attention on the gene organization. In contrast to most IEGs, which have genes that are <5 kb, the Homer 1 gene was found to span approximately 100 kb. The constitutive Homer 1b/c forms are encoded by exons 1-10, whereas the IEG forms are encoded by exons 1-5 and parts of intron 5. RNase protection demonstrated a >10-fold activity-dependent increase in mRNA levels exclusively for the IEG forms. Moreover, fluorescent in situ hybridization documented that new primary Homer 1 transcripts are induced in neuronal nuclei within a few minutes after seizure, typical of IEGs, and that Homer 1b-specific exons are excluded from the activity-induced transcripts. Thus, at the resting state of the neurons, the entire gene is constitutively transcribed at low levels to yield Homer 1b/c transcripts. Neuronal activity sharply increases the rate of transcription initiation, with most transcripts now ending within the central intron. These coordinate transcriptional events rapidly convert a constitutive gene to an IEG and regulate the expression of functionally different Homer 1 proteins.

    Funded by: NIA NIH HHS: AG09219; NIDA NIH HHS: DA11742; NIMH NIH HHS: KO2 MH01153, MH60123

    The Journal of neuroscience : the official journal of the Society for Neuroscience 2002;22;1;167-75

  • Expression of vesl-1S/homer-1a, a gene associated with long-term potentiation, in the brain of the epileptic EI mouse.

    Morioka R, Kato A, Fueta Y and Sugiyama H

    Department of Biology, Faculty of Science, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.

    The El mouse is an animal model for hereditary epilepsy. It undergoes a convulsive seizure lasting 10-30 s after vestibular stimulation, such as "tossing-up". To better characterize the effects of seizure activity in the El mouse, we examined the expression profile of vesl-1S/homer-1a mRNA in the brain. It has been shown that this mRNA is expressed after long-term potentiation or seizures induced by electrical or pharmacological stimulations. The basal level of vesl-1S mRNA was very low even in seizure-susceptible El mice. The El mouse hippocampus, but not that of ddY mice, showed a remarkable increase in vesl-1S mRNA expression in the dentate granule cell layer after seizure induced by "tossing-up". The mRNA remained for about 3 h after the seizure and disappeared after 8 h.

    Neuroscience letters 2001;313;1-2;99-101

  • Homer: a link between neural activity and glutamate receptor function.

    Xiao B, Tu JC and Worley PF

    Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

    The proteins of the Homer family bind to proline-rich sequences in group I metabotropic glutamate receptors, inositol trisphosphate receptors, ryanodine receptors, and Shank family proteins. Homer proteins also self associate and function as adaptors to couple interacting proteins. Recent observations indicate a role for Homer complexes in signal transduction, synaptogenesis and receptor trafficking.

    Current opinion in neurobiology 2000;10;3;370-4

  • Cupidin, an isoform of Homer/Vesl, interacts with the actin cytoskeleton and activated rho family small GTPases and is expressed in developing mouse cerebellar granule cells.

    Shiraishi Y, Mizutani A, Bito H, Fujisawa K, Narumiya S, Mikoshiba K and Furuichi T

    Department of Molecular Neurobiology, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

    A developmentally regulated Homer/Vesl isoform, Cupidin (Homer 2a/Vesl-2Delta11), was isolated from postnatal mouse cerebellum using a fluorescent differential display strategy. The strongest expression of Cupidin was detected in the cerebellar granule cells at approximately postnatal day 7. Cupidin was enriched in the postsynaptic density fraction, and its immunoreactivity was concentrated at glomeruli of the inner granular layer when active synaptogenesis occurred. Cupidin protein could be divided into two functional domains: the N-terminal portion, which was highly conserved among Homer/Vesl family proteins, and the C-terminal portion, which consisted of a putative coiled-coil structure, including several leucine zipper motifs. The N-terminal fragment of Cupidin, which was able to associate with metabotropic glutamate receptor 1 (mGluR1), also interacted with F-actin in vitro. In keeping with this, F-actin immunocytochemically colocalized with Cupidin in cultured cerebellar granule cells, and a Cupidin-mGluR1-actin complex was immunoprecipitated from crude cerebellar lysates using an anti-Cupidin antibody. On the other hand, the C-terminal portion of Cupidin bound to Cdc42, a member of Rho family small GTPases, in a GTP-dependent manner in vitro, and Cupidin functionally interacted with activated-Cdc42 in a heterologous expression system. Together, our findings indicate that Cupidin may serve as a postsynaptic scaffold protein that links mGluR signaling with actin cytoskeleton and Rho family proteins, perhaps during the dynamic phase of morphological changes that occur during synapse formation in cerebellar granule cells.

    The Journal of neuroscience : the official journal of the Society for Neuroscience 1999;19;19;8389-400

  • Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors.

    Tu JC, Xiao B, Yuan JP, Lanahan AA, Leoffert K, Li M, Linden DJ and Worley PF

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    Group I metabotropic glutamate receptors (mGluRs) activate PI turnover and thereby trigger intracellular calcium release. Previously, we demonstrated that mGluRs form natural complexes with members of a family of Homer-related synaptic proteins. Here, we present evidence that Homer proteins form a physical tether linking mGluRs with the inositol trisphosphate receptors (IP3R). A novel proline-rich "Homer ligand" (PPXXFr) is identified in group 1 mGluRs and IP3R, and these receptors coimmunoprecipitate as a complex with Homer from brain. Expression of the IEG form of Homer, which lacks the ability to cross-link, modulates mGluR-induced intracellular calcium release. These studies identify a novel mechanism in calcium signaling and provide evidence that an IEG, whose expression is driven by synaptic activity, can directly modify a specific synaptic function.

    Funded by: NIDA NIH HHS: DA 10309, DA 11742; NIMH NIH HHS: KO2 MH01152; ...

    Neuron 1998;21;4;717-26

  • Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins.

    Xiao B, Tu JC, Petralia RS, Yuan JP, Doan A, Breder CD, Ruggiero A, Lanahan AA, Wenthold RJ and Worley PF

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

    Homer is a neuronal immediate early gene (IEG) that is enriched at excitatory synapses and binds group 1 metabotropic glutamate receptors (mGluRs). Here, we characterize a family of Homer-related proteins derived from three distinct genes. Like Homer IEG (now termed Homer 1a), all new members bind group 1 mGluRs. In contrast to Homer 1a, new members are constitutively expressed and encode a C-terminal coiled-coil (CC) domain that mediates self-multimerization. CC-Homers form natural complexes that cross-link mGluRs and are enriched at the postsynaptic density. Homer 1a does not multimerize and blocks the association of mGluRs with CC-Homer complexes. These observations support a model in which the dynamic expression of Homer 1a competes with constitutively expressed CC-Homers to modify synaptic mGluR properties.

    Funded by: NIDA NIH HHS: DA10309, DA11742; NIMH NIH HHS: KO2 MH01152; ...

    Neuron 1998;21;4;707-16

Gene lists (9)

Gene List Source Species Name Description Gene count
L00000001 G2C Mus musculus Mouse PSD Mouse PSD adapted from Collins et al (2006) 1080
L00000005 G2C Mus musculus Mouse mGluR5 Mouse mGluR5 complex adapted from Collins et al (2006) 52
L00000007 G2C Mus musculus Mouse NRC Mouse NRC adapted from Collins et al (2006) 186
L00000008 G2C Mus musculus Mouse PSP Mouse PSP adapted from Collins et al (2006) 1121
L00000020 G2C Mus musculus Pocklington M2 Cluster 2 (mouse) from Pocklington et al (2006) 13
L00000060 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-CONSENSUS Human cortex PSD consensus (ortho) 748
L00000062 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-CONSENSUS Mouse cortex PSD consensus 984
L00000070 G2C Mus musculus BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list (ortho) 1461
L00000072 G2C Mus musculus BAYES-COLLINS-MOUSE-PSD-FULL Mouse cortex PSD full list 1556
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

Cookies Policy | Terms and Conditions. This site is hosted by Edinburgh University and the Genes to Cognition Programme.