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HGNC Approved Gene Symbol: HOMER1
Cytogenetic location: 5q14.1 Genomic coordinates (GRCh38) : 5:79,372,636-79,514,134 (from NCBI)
L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors (mGluRs). Group I mGluRs (see GRM1, 604473, and GRM5, 604102) are 7-membrane-spanning proteins that activate phosphatidylinositol turnover and thereby trigger intracellular calcium release. HOMER1 is a neuronal immediate-early gene (IEG) that is enriched at excitatory synapses and binds mGluRs (Brakeman et al., 1997; Xiao et al., 1998).
Brakeman et al. (1997) identified the IEG Homer, which encodes a protein with PDZ-like and Enabled (609061)/VASP (601703) homology-1 (EVH1) domains that binds to the C terminus of phosphoinositide-linked GRMs.
By screening rodent brain cDNA libraries with the Homer sequence reported by Brakeman et al. (1997), Homer1a, and by database searches, Xiao et al. (1998) identified several Homer-related sequences: splice variants of Homer1a, termed Homer1b and Homer1c, as well as the novel genes Homer2 (604799) and Homer3 (604800). Analysis of the deduced protein sequences revealed that they are highly homologous to the 186-amino acid Homer1a in the N terminus, where group I GRM-binding is mediated. Homer1a possesses a long 3-prime UTR with multiple destabilizing repeat sequences typical of immediate early genes, whereas the subsequently identified Homer family members have a short 3-prime UTR without the repeats, are constitutively expressed in brain, and encode a C-terminal coiled coil (CC) multimerization motif. The cDNA for mouse Homer1b encodes a deduced 354-amino acid protein that is 100% identical to Homer1a in the 175-amino acid N terminus. Homer1c has an insertion of 12 amino acids between the conserved N terminus and the CC domain. In situ hybridization analysis revealed that, like Homer1a, Homer1b and -1c are expressed at high levels in hippocampus, striatum, and cortex. Immunoblots revealed expression of Homer1b in cortex, hippocampus, and cerebellum, with moderate expression in heart and kidney and weaker expression in liver. Immunoblot and immunohistochemical analyses showed that Homer1b is enriched in the postsynaptic density.
Unlike Homer1a, Homer1b and -1c are not significantly upregulated in response to electroconvulsive seizure (Xiao et al., 1998). Coimmunoprecipitation experiments showed that Homer1b is associated with Homer-3 in cerebellum, most likely through the CC domains since the N terminus is monovalent in its binding to GRM. However, GRMs are selectively uncoupled from Homer1b when Homer1a is expressed. Xiao et al. (1998) concluded that CC-Homers form natural complexes crosslinking GRMs and mediating protein-protein interactions, including self-multimerization. Homer1a, on the other hand, competes with the constitutively expressed CC-Homers, with the exception of Homer2b, to modify synaptic GRM properties, such as linkage of GRMs to the inositol triphosphate receptors (e.g., ITPR1, 147265).
Using database searches and coimmunoprecipitation, mutation, and immunoblot analyses, Tu et al. (1998) identified other proteins involved in calcium signaling (e.g., ITPR1) to which Homer1b binds. These proteins express a novel proline-rich 'Homer ligand' (PPXXFR). The ability of GRMs to evoke calcium responses is decreased in the presence of Homer1a. Mutation analysis showed that the amino acids most critical for binding are the proline residues and not the phenylalanine residues that are critical in the similar SH3 motif.
Using immunofluorescence and biochemical analyses, Roche et al. (1999) showed that Homer1b, which the authors termed H1b, causes GRM1/5 to be retained in the endoplasmic reticulum. In the absence of H1b but not H1a, possibly because of the absence of a coiled coil domain, GRM1/5 travels through the secretory pathway to the plasma membrane.
Tu et al. (1999) identified a Homer-binding domain in rat Shank (SHANK1; 604999). Shank and Homer coimmunoprecipitated from rat brain and colocalized at the postsynaptic density (PSD). Shank also clustered mGluR5 (138245) in heterologous cells in the presence of Homer and mediated the coclustering of Homer with PSD95 (DLG4; 602887)/GKAP (DLGAP1; 605445). Tu et al. (1999) concluded that Shank may crosslink Homer and PSD95 complexes in the PSD and mediate mGluR and NMDA receptor signaling.
G protein-coupled receptors (GPCRs) transduce signals from extracellular transmitters to the inside of the cell by activating G proteins. Mutation and overexpression of these receptors have revealed that they can reach their active state even in the absence of agonist, as a result of a natural shift in the equilibrium between their inactive and active conformations. Such agonist-independent (constitutive) activity has been observed for the glutamate GPCRs (the metabotropic glutamate receptors mGluR1a and mGluR5) when they are overexpressed in heterologous cells. Ango et al. (2001) demonstrated that in neurons, the constitutive activity of these receptors is controlled by Homer proteins, which bind directly to the receptors' carboxy-terminal intracellular domains. Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a, induces constitutive activity in mGluR1a or mGluR5. Ango et al. (2001) concluded that these glutamate GPCRs can be directly activated by intracellular proteins as well as by agonists.
One prominent action of group I mGluRs is to protect neurons from apoptotic death. Using immunoprecipitation studies in rat, Rong et al. (2003) found that the protein kinase enhancer PIKE-L (605476) binds to Homer1c. Activation of mGluR5 enhanced formation of an mGluRI-Homer-PIKE-L complex, leading to activation of PI3K activity and prevention of apoptosis in cultured neurons.
Using rat Homer1b, human HOMER3A, and rat Shank, Hayashi et al. (2009) showed that Homer and Shank formed a mesh-like matrix structure. X-ray crystallographic analysis of the Homer coiled-coil region suggested that Homer assumes a tetrameric structure in which the C-terminal coiled-coil regions of 2 Homer molecules intercalate with the C-terminal coiled-coil regions of 2 other Homer molecules in a tail-to-tail fashion. The elongated tetramer is then capped at each end with 2 Homer N-terminal EVH1 domains. In cultured hippocampal neurons, Homer tetramerization was required for structural integrity of dendritic spines and recruitment of proteins to synapses.
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. Okada et al. (2009) found that in rat neurons, soma-derived Vesl1S (Homer1a) 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 Vesl1S proteins, which met many criteria for synaptic tagging. Okada et al. (2009) concluded that Vesl1S supports the hypothesis and that the activity-dependent regulation of spine entry functions as a synaptic tag.
Using biochemistry, proteomics, and imaging in mice, Diering et al. (2017) found that during sleep, synapses undergo widespread alterations in composition and signaling, including weakening of synapses through removal and dephosphorylation of synaptic AMPA-type glutamate receptors. These changes are driven by the immediate-early gene Homer1a and signaling from group I metabotropic glutamate receptors mGluR1 (604473) and mGluR5 (604102), respectively. Homer1a serves as a molecular integrator of arousal and sleep need via the wake- and sleep-promoting neuromodulators noradrenaline and adenosine, respectively. Diering et al. (2017) concluded that their data suggested that homeostatic scaling-down, a global form of synaptic plasticity, is active during sleep to remodel synapses and participates in the consolidation of contextual memory.
Norton et al. (2003) determined that the HOMER1 gene has 9 exons.
Norton et al. (2003) stated that the HOMER1 gene maps to chromosome 5q14.2.
Szumlinski et al. (2004) found that deletion of homer1 and homer2 in mice enhanced cocaine-induced locomotion and conditioned reward, as measured by the conditioned place preference response, compared to wildtype mice. Homer1 and homer2 knockout mice had a 50% decrease in basal extracellular glutamate in the nucleus accumbens compared to wildtype mice and showed an increase in extracellular glutamate in response to acute cocaine injection. These effects were not observed for dopamine. Adenoviral-mediated restoration of homer2 in the homer2-knockout mice reversed the cocaine-sensitized phenotype. The findings were similar to those observed in rats withdrawn from repeated cocaine administration, which showed a reduction in homer1 expression in the nucleus accumbens (Swanson et al., 2001). Szumlinski et al. (2004) concluded that homer1 and homer2 may play a role in regulating cocaine addiction.
Using rodent models of unilateral hindpaw inflammation, Tappe et al. (2006) found that Homer1a was rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor (GRIN1; 138249)-dependent manner. Homer1a strongly attenuated calcium mobilization and MAP kinase (e.g., MAPK3; 601795) activation induced by glutamate receptors. Preventing activity-induced upregulation of Homer1a with short interfering hairpin RNAs in mice exacerbated inflammatory pain. Targeted gene transfer of Homer1a to specific spinal segments reduced inflammatory hyperalgesia. Tappe et al. (2006) concluded that HOMER1 is involved in pain plasticity and may be a target for treatment of chronic inflammatory pain.
Using expression profiling in inbred mouse strains, Maret et al. (2007) showed that sleep deprivation induced changes in brain gene expression for a few genes only, most notably overexpression of Homer1a.
Bangash et al. (2011) reported an analysis of a mouse genetic model that deletes the C terminus of Shank3 to mimic human mutations that cause autism spectrum disorder; however, their paper was retracted due to improperly assembled figure panels.
Ango, F., Prezeau, L., Muller, T., Tu, J. C., Xiao, B., Worley, P. F., Pin, J. P., Bockaert, J., Fagni, L. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 411: 962-965, 2001. [PubMed: 11418862] [Full Text: https://doi.org/10.1038/35082096]
Bangash, M. A., Park, J. M., Melnikova, T., Wang, D., Jeon, S. K., Lee, D., Syeda, S., Kim, J., Kouser, M., Schwartz, J., Cui, Y., Zhao, X., and 10 others. Enhanced polyubiquitination of Shank3 and NMDA receptor in a mouse model of autism. Cell 145: 758-772, 2011. Note: Retraction: Cell 152: 367 only, 2013. [PubMed: 21565394] [Full Text: https://doi.org/10.1016/j.cell.2011.03.052]
Brakeman, P. R., Lanahan, A. A., O'Brien, R., Roche, K., Barnes, C. A., Huganir, R. L., Worley, P. F. Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386: 284-288, 1997. [PubMed: 9069287] [Full Text: https://doi.org/10.1038/386284a0]
Diering, G. H., Nirujogi, R. S., Roth, R. H., Worley, P. F., Pandey, A., Huganir, R. L. Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science 355: 511-515, 2017. [PubMed: 28154077] [Full Text: https://doi.org/10.1126/science.aai8355]
Hayashi, M. K., Tang, C., Verpelli, C., Narayanan, R., Stearns, M. H., Xu, R.-M., Li, H., Sala, C., Hayashi, Y. The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell 137: 159-171, 2009. [PubMed: 19345194] [Full Text: https://doi.org/10.1016/j.cell.2009.01.050]
Maret, S., Dorsaz, S., Gurcel, L., Pradervand, S., Petit, B., Pfister, C., Hagenbuchle, O., O'Hara, B. F., Franken, P., Tafti, M. Homer1a is a core brain molecular correlate of sleep loss. Proc. Nat. Acad. Sci. 104: 20090-20095, 2007. [PubMed: 18077435] [Full Text: https://doi.org/10.1073/pnas.0710131104]
Norton, N., Williams, H. J., Williams, N. M., Spurlock, G., Zammit, S., Jones, G., Jones, S., Owen, R., O'Donovan, M. C., Owen, M. J. Mutation screening of the Homer gene family and association analysis in schizophrenia. Am. J. Med. Genet. 120B: 18-21, 2003. [PubMed: 12815733] [Full Text: https://doi.org/10.1002/ajmg.b.20032]
Okada, D., Ozawa, F., Inokuchi, K. Input-specific spine entry of soma-derived Vesl-1S protein conforms to synaptic tagging. Science 324: 904-909, 2009. [PubMed: 19443779] [Full Text: https://doi.org/10.1126/science.1171498]
Roche, K. W., Tu, J. C., Petralia, R. S., Xiao, B., Wenthold, R. J, Worley, P. F. Homer 1b regulates the trafficking of group I metabotropic glutamate receptors. J. Biol. Chem. 274: 25953-25957, 1999. [PubMed: 10464340] [Full Text: https://doi.org/10.1074/jbc.274.36.25953]
Rong, R., Ahn, J.-Y., Huang, H., Nagata, E., Kalman, D., Kapp, J. A., Tu, J., Worley, P. F., Snyder, S. H., Ye, K. PI3 kinase enhancer-Homer complex couples mGluRI to PI3 kinase, preventing neuronal apoptosis. Nature Neurosci. 6: 1153-1161, 2003. [PubMed: 14528310] [Full Text: https://doi.org/10.1038/nn1134]
Swanson, C. J., Baker, D. A., Carson, D., Worley, P. F., Kalivas, P. W. Repeated cocaine administration attenuates group I metabotropic glutamate receptor-mediated glutamate release and behavioral activation: a potential role for homer. J. Neurosci. 21: 9043-9052, 2001. [PubMed: 11698615] [Full Text: https://doi.org/10.1523/JNEUROSCI.21-22-09043.2001]
Szumlinski, K. K., Dehoff, M. H., Kang, S. H., Frys, K. A., Lominac, K. D., Klugmann, M., Rohrer, J., Griffin, W., III, Toda, S., Champtiaux, N. P., Berry, T., Tu, J. C., Shealy, S. E., During, M. J., Middaugh, L. D., Worley, P. F., Kalivas, P. W. Homer proteins regulate sensitivity to cocaine. Neuron 43: 401-413, 2004. [PubMed: 15294147] [Full Text: https://doi.org/10.1016/j.neuron.2004.07.019]
Tappe, A., Klugmann, M., Luo, C., Hirlinger, D., Agarwal, N., Benrath, J., Ehrengruber, M. U., During, M. J., Kuner, R. Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain. Nature Med. 12: 677-681, 2006. [PubMed: 16715092] [Full Text: https://doi.org/10.1038/nm1406]
Tu, J. C., Xiao, B., Naisbitt, S., Yuan, J. P., Petralia, R. S., Brakeman, P., Doan, A., Aakalu, V. K., Lanahan, A. A., Sheng, M., Worley, P. F. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23: 583-892, 1999. [PubMed: 10433269] [Full Text: https://doi.org/10.1016/s0896-6273(00)80810-7]
Tu, J. C., Xiao, B., Yuan, J. P., Lanahan, A. A., Leoffert, K., Li, M., Linden, D. J., Worley, P. F. Homer binds a novel proline-rich motif and links group 1 metabotropic glutamate receptors with IP3 receptors. Neuron 21: 717-726, 1998. [PubMed: 9808459] [Full Text: https://doi.org/10.1016/s0896-6273(00)80589-9]
Xiao, B., Tu, J. C., Petralia, R. S., Yuan, J. P., Doan, A., Breder, C. D., Ruggiero, A., Lanahan, A. A., Wenthold, R. J., Worley, P. F. Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins. Neuron 21: 707-716, 1998. [PubMed: 9808458] [Full Text: https://doi.org/10.1016/s0896-6273(00)80588-7]