Homer Proteins Research Articles

Conditions associated with ER dysfunction activate homer 1a expression.

Homer proteins physically link metabotropic glutamate receptors with IP3 receptors located at the endoplasmic reticulum (ER) and thereby modulate receptor-activated calcium signaling. Homer 1a, the short form of constitutively expressed homer 1 proteins, exerts dominant negative activity with respect to homer 1 proteins by interfering with the formation of multiprotein complexes. Homer 1a is an immediate early gene, the expression of which is activated by various stimuli including glutamate receptor activation. The mechanisms underlying activation of homer 1a expression are however, not fully understood. Here, we show that homer 1a expression is induced in neuronal cell cultures under experimental conditions associated with ER dysfunction. Increased homer 1a mRNA levels were found in 2 sets of cultures: in those exposed to thapsigargin, a specific inhibitor of ER Ca2+-ATPase, after a transient depletion of ER calcium stores through exposure to calcium-free medium supplemented with EGTA, and in those exposed to a proteasome inhibitor known to induce ER dysfunction. Thus, homer 1a expression may be activated by impairment of ER functioning just as it is by glutamate receptor activation.

Control of constitutive activity of metabotropic glutamate receptors by Homer proteins

Abstract The postsynaptic metabotropic glutamate receptor subtypes 1a and 5 (mGluR1a and mGluR5) control excitatory synaptic transmission in the mammalian brain. These receptors are coupled to inositol trisphosphate- and ryanodine-sensitive Ca2+ stores via G proteins. The scaffolding protein Homer1b, Homer1c, Homer2, or Homer3 physically links mGluR1a or mGluR5 to these intracellular Ca2+ stores. The short splice variant Homer1a represents an exception within the family of Homer proteins. This protein is the product of an immediate early gene induced after intense neuronal activity that disrupts the mGluR1a/5–Ca2+ store scaffold. In the absence of agonist, Homer3 stabilizes mGluR1a and mGluR5 in an inactivate state, whereas Homer1a competes with Homer3 on mGluR1a and mGluR5, and directly activates these receptors. This is the first evidence showing that an intracellular protein can induce a constitutive activity of a G protein-coupled receptor, in response to intrinsic neuronal activity.

Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons.

The molecular basis for the known intramembrane receptor/receptor interactions among G protein-coupled receptors was postulated to be heteromerization based on receptor subtype-specific interactions between different types of receptor homomers. The discovery of GABAB heterodimers started this field rapidly followed by the discovery of heteromerization among isoreceptors of several G protein-coupled receptors such as delta/kappa opioid receptors. Heteromerization was also discovered among distinct types of G protein-coupled receptors with the initial demonstration of somatostatin SSTR5/dopamine D2 and adenosine A1/dopamine D1 heteromeric receptor complexes. The functional meaning of these heteromeric complexes is to achieve direct or indirect (via adapter proteins) intramembrane receptor/receptor interactions in the complex. G protein-coupled receptors also form heteromeric complexes involving direct interactions with ion channel receptors, the best example being the GABAA/dopamine D5 receptor heteromerization, as well as with receptor tyrosine kinases and with receptor activity modulating proteins. As an example, adenosine, dopamine, and glutamate metabotropic receptor/receptor interactions in the striatopallidal GABA neurons are discussed as well as their relevance for Parkinson's disease, schizophrenia, and drug dependence. The heterodimer is only one type of heteromeric complex, and the evidence is equally compatible with the existence of higher order heteromeric complexes, where also adapter proteins such as homer proteins and scaffolding proteins can exist. These complexes may assist in the process of linking G protein-coupled receptors and ion channel receptors together in a receptor mosaic that may have special integrative value and may constitute the molecular basis for some forms of learning and memory.

Homer 2 tunes G protein-coupled receptors stimulus intensity by regulating RGS proteins and PLCbeta GAP activities.

Homers are scaffolding proteins that bind G protein–coupled receptors (GPCRs), inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs), ryanodine receptors, and TRP channels. However, their role in Ca2+ signaling in vivo is not known. Characterization of Ca2+ signaling in pancreatic acinar cells from Homer2−/− and Homer3−/− mice showed that Homer 3 has no discernible role in Ca2+ signaling in these cells. In contrast, we found that Homer 2 tunes intensity of Ca2+ signaling by GPCRs to regulate the frequency of [Ca2+]i oscillations. Thus, deletion of Homer 2 increased stimulus intensity by increasing the potency for agonists acting on various GPCRs to activate PLCβ and evoke Ca2+ release and oscillations. This was not due to aberrant localization of IP3Rs in cellular microdomains or IP3R channel activity. Rather, deletion of Homer 2 reduced the effectiveness of exogenous regulators of G proteins signaling proteins (RGS) to inhibit Ca2+ signaling in vivo. Moreover, Homer 2 preferentially bound to PLCβ in pancreatic acini and brain extracts and stimulated GAP activity of RGS4 and of PLCβ in an in vitro reconstitution system, with minimal effect on PLCβ-mediated PIP2 hydrolysis. These findings describe a novel, unexpected function of Homer proteins, demonstrate that RGS proteins and PLCβ GAP activities are regulated functions, and provide a molecular mechanism for tuning signal intensity generated by GPCRs and, thus, the characteristics of [Ca2+]i oscillations.

Vesl/Homer proteins regulate ryanodine receptor type 2 function and intracellular calcium signaling

Cellular signaling proteins such as metabotropic glutamate receptors, Shank, and different types of ion channels are physically linked by Vesl (VASP/Ena-related gene up-regulated during seizure and LTP)/Homer proteins [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23 (2000) 80; J. Cell Sci. 113 (2000) 1851]. Vesl/Homer proteins have also been implicated in differentiation and physiological adaptation processes [Nat. Neurosci. 4 (2001) 499; Nature 411 (2001) 962; Biochem. Biophys. Res. Commun. 279 (2000) 348]. Here we provide evidence that a Vesl/Homer subtype, Vesl-1L/Homer-1c (V-1L), reduces the function of the intracellular calcium channel ryanodine receptor type 2 (RyR2). In contrast, Vesl-1S/Homer-1a (V-1S) had no effect on RyR2 function but reversed the effects of V-1L. In live cells, in calcium release studies and in single-channel electrophysiological recordings of RyR2, V-1L reduced RyR2 activity. Important physiological functions and pharmacological properties of RyR2 are preserved in the presence of V-1L. Our findings demonstrate that a protein-protein interaction between V-1L and RyR2 is not only necessary for organizing the structure of intracellular calcium signaling proteins [Curr. Opin. Neurobiol. 10 (2000) 370; Trends Neurosci. 23(2000)80; J. Cell Sci. 113 (2000) 1851; Nat Neurosci. 4 (2001) 499; Nature 411 (2001) 962; Biochem. Biophys. Res. Commun. 279 (2000) 348; Nature 386 (1997) 284], but that V-1L also directly regulates RyR2 channel activity by changing its biophysical properties. Thereby it may control cellular calcium homeostasis. These observations suggest a novel mechanism for the regulation of RyR2 and calcium-dependent cellular functions.

Antipsychotics with different D2 dopamine receptor potency affect differently the postsynaptic density protein homer at glutamatergic metabotropic synapse

Melanoma is an aggressive cutaneous cancer, whose incidence is growing in recent years, especially in the younger population. The favorable therapy for this neoplasm consists in its early surgical excision; otherwise, in case of late diagnosis, melanoma becomes very refractory to any conventional therapy. Nevertheless, the acute inflammatory response occurring after excision of the primary melanoma can affect the activation and/or regulation of melanoma invasion and metastasis. Nonsteroidal anti-inflammatory drugs (NSAIDs), widely employed in clinical therapy as cyclooxygenase inhibitors, also display a cytotoxic effect on some cancer cell lines; therefore, their possible usage in combination with conventional chemo- and radio-therapies of tumors is being considered. In particular, diclofenac, one of the most common NSAIDs, displays its anti-proliferative effect in many tumor lines, through an alteration of the cellular redox state. In this study, the possible anti-neoplastic potential of diclofenac on the human melanoma cell lines A2058 and SAN was investigated, and a comparison was made with the results obtained from the nonmalignant fibroblast cell line BJ-5ta. Either in A2058 or SAN, the diclofenac treatment caused typical apoptotic morphological changes, as well as an increase of the number of sub-diploid nuclei; conversely, the same treatment on BJ-5ta had only a marginal effect. The observed decrease of Bcl-2/Bax ratio and a parallel increase of caspase-3 activity confirmed the pro-apoptotic role exerted by diclofenac in melanoma cells; furthermore, the drug provoked an increase of the ROS levels, a decrease of mitochondrial superoxide dismutase (SOD2), the cytosolic translocation of both SOD2 and cytochrome c, and an increase of caspase-9 activity. Finally, the cytotoxic effect of diclofenac was amplified, in melanoma cells, by the silencing of SOD2. These data improve the knowledge on the effects of diclofenac and suggest that new anti-neoplastic treatments should be based on the central role of mitochondrion in cancer development; under this concern, the possible involvement of SOD2 as a novel target could be considered.

Coincidence in dendritic clustering and synaptic targeting of homer proteins and NMDA receptor complex proteins NR2B and PSD95 during development of cultured hippocampal neurons

Homer is a scaffold protein that binds glutamate receptor complexes and actin cytoskeleton in postsynapses. The present study analyzed developmental changes in subcellular localization of Homer proteins in cultured hippocampal neurons. All three Homer family proteins, Homer 1b/c, Cupidin/Homer 2, and Homer 3, not only form heteromeric coclusters, but also localize close to the NMDA receptor complex including the NR2B subunit and PSD95 throughout dendritic and synaptic differentiation. Synaptic clustering of Homer proteins is enhanced by simultaneous blockade of NMDA receptor and cAMP phosphodiesterase activities, as is clustering of NMDA receptors. Homer proteins colocalize with actin-cytoskeletal proteins F-actin and Drebrin partially during the middle stage and to a greater extent in the late stage, and with the GluR1 subunit of AMPA receptors only in the late stage. Clustering sites of Homer are not synaptic in early-middle stages, but become synaptic in the late stage, as deduced from synaptic targeting of Bassoon, Synaptophysin, and N-cadherin. Our results indicate a coincidence in dendritic clustering in addition to developmental and activity-regulated synaptic targeting between Homer and the NMDA receptor complex.

More Versatility of Homer

Homer proteins have been characterized as adaptor proteins in signaling complexes associated with metabotropic glutamate receptors. Homer proteins bind both the receptor and inositol 1,4,5-trisphosphate receptors in these complexes. Noting that Ryanodine receptor type 1 (RyR1) also has a putative Homer-binding sequence, Feng et al. explored the functional relation of these proteins. Endogenous Homer proteins could be immunoprecipitated with RyR1 from extracts of rat skeletal muscle. Recordings from single RyR1 channels reconstituted in bilayer lipid membranes showed that Homer proteins enhanced the open probability of the RyR1 channel. Assays with sarcoplasmic reticulum vesicles from skeletal muscle showed that Homer proteins increased efficacy of Ca 2+ and caffeine in activating RyR1. Although the truncated, short form of Homer1 is thought to function in a dominant-negative manner in some systems, both the long and short forms of Homer1 had similar effects on the RyR1 channel. The authors discuss this new role of Homer in regulating the gain of excitation-contraction coupling in muscle cells. For more on Homer, see the STKE Review by Fagni et al. W. Feng, J. Tu, T. Yang, P. S. Vernon, P. D. Allen, P. F. Worley, I. N. Pessah. Homer regulates gain of ryanodine receptor type 1 channel complex. J. Biol. Chem. 277, 44722-44730 (2002). [Abstract] [Full Text] L. Fagni, P. F. Worley, F. Ango, Homer as both a scaffold and transduction molecule. Science's STKE (2002), http://stke.sciencemag.org/cgi/content/full/sigtrans;2002/137/re8 [Abstract] [Full Text]

Homer Regulates Gain of Ryanodine Receptor Type 1 Channel Complex

Homer proteins form an adapter system that regulates coupling of group 1 metabotropic glutamate receptors with intracellular inositol trisphosphate receptors and is modified by neuronal activity. Here, we demonstrate that Homer proteins also physically associate with ryanodine receptors type 1 (RyR1) and regulate gating responses to Ca(2+), depolarization, and caffeine. In contrast to the prevailing notion of Homer function, Homer1c (long form) and Homer1-EVH1 (short form) evoke similar changes in RyR activity. The EVH1 domain mediates these actions of Homer and is selectively blocked by a peptide that mimics the Homer ligand. 1B5 dyspedic myotubes expressing RyR1 with a point mutation of a putative Homer-binding domain exhibit significantly reduced (approximately 33%) amplitude in their responses to K(+) depolarization compared with cells expressing wild type protein. These results reveal that in addition to its known role as an adapter protein, Homer is a direct modulator of Ca(2+) release gain. Homer is the first example of an "adapter" that also modifies signaling properties of its target protein. The present work reveals a novel mechanism by which Homer directly modulates the function of its target protein RyR1 and excitation-contraction coupling in skeletal myotubes. This form of regulation may be important in other cell types that express Homer and RyR1.

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

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.

Homer-1 mRNA in the rat suprachiasmatic nucleus is regulated differentially by the retinohypothalamic tract transmitters pituitary adenylate cyclase activating polypeptide and glutamate at time points where light phase-shifts the endogenous rhythm

The suprachiasmatic nucleus (SCN) generates circadian rhythms which are synchronised to the environmental light/dark cycle via the retinohypothalamic tract (RHT). Pituitary adenylate cyclase activating polypeptide (PACAP) and glutamate, two transmitters co-stored in the rat retinohypothalamic tract, are involved in photic entrainment of the circadian pacemaker, but their functional interplay is poorly understood. Homer proteins are involved in glutamatergic receptor function and signalling. By quantitative in situ hybridisation histochemistry we found that light stimulation of rats at early and late night induced Homer-1 gene expression in the SCN at time points where light induces phase-delay or phase-advance, respectively. Using a rat brain slice model Homer-1 mRNA levels in the SCN displayed a modest diurnal variation similar to that in vivo. The changes in Homer-1 gene expression after in vitro stimulation with PACAP and/or glutamate differed at early and late night. Nanomolar PACAP induced Homer-1 gene expression at both early and late night while glutamate was only able to increase Homer-1 mRNA level at early night. PACAP in micromolar concentration had no effect per se, but inhibited the glutamate induced Homer-1 response at early night, while at late night co-administration of PACAP and glutamate mediated a slight induction of Homer-1 gene expression. In conclusion, the RHT transmitters PACAP and glutamate could be responsible for the light-induced expression of Homer-1 in the SCN, and Homer-1 seems to be differentially regulated by the two transmitters at early and late night.

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

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.

Homer as both a scaffold and transduction molecule.

Increasing evidence shows that scaffold proteins not only control membrane assembly of receptors and channels, but also modulate intracellular signaling by assembled receptors. The Homer family of proteins act as scaffolds to bind clusters of proteins and glutamate receptors at postsynaptic sites. We review results of cloning and gene expression of this protein family, and summarize roles in glutamate receptor function and intracellular signaling in neurons. Homer proteins trigger the localization of metabotropic glutamate receptor subtype 5 (mGlu5 receptor) to the postsynaptic plasma membrane. They can also alter the kinetics and peak amplitude of the intracellular Ca2+ responses of mGlu1 and mGlu5 receptors. Homer proteins can either prevent or promote spontaneous activation of these receptors, depending on the type of Homer protein isoform expressed.

Homer as Both a Scaffold and Transduction Molecule

Increasing evidence shows that scaffold proteins not only control membrane assembly of receptors and channels, but also modulate intracellular signaling by assembled receptors. The Homer family of proteins act as scaffolds to bind clusters of proteins and glutamate receptors at postsynaptic sites. We review results of cloning and gene expression of this protein family, and summarize roles in glutamate receptor function and intracellular signaling in neurons. Homer proteins trigger the localization of metabotropic glutamate receptor subtype 5 (mGlu5 receptor) to the postsynaptic plasma membrane. They can also alter the kinetics and peak amplitude of the intracellular Ca2+ responses of mGlu1 and mGlu5 receptors. Homer proteins can either prevent or promote spontaneous activation of these receptors, depending on the type of Homer protein isoform expressed.

Homer-Dependent Cell Surface Expression of Metabotropic Glutamate Receptor Type 5 in Neurons

The metabotropic glutamate (mGlu) receptors are a family of receptors involved in the tuning of fast excitatory synaptic transmission in the brain. Experiments performed in heterologous expression systems suggest that cell surface expression of group I mGlu receptors is controlled by their auxiliary protein, Homer. However, whether or not this also applies to neurons remains controversial. Here we show that in cultured cerebellar granule cells, the group I mGlu receptor subtype, mGlu5, transfected alone is functionally expressed at the surface of these neurons. Transfected Homer1b caused intracellular retention and clustering of this receptor at synaptic sites. Recombinant Homer1a alone did not affect cell surface expression of the receptor, but in neurons transfected with Homer1b, excitation-induced expression of native Homer1a reversed the intracellular retention of mGlu5 receptors, resulting in the receptor trafficking to synaptic membranes. Transfected Homer1a also increased the latency and amplitude of the mGlu5 receptor Ca2+ response. These results indicate that Homer1 proteins regulate synaptic cycling and Ca2+ signaling of mGlu5 receptors, in response to neuronal activity.

Modulation of synaptic signalling complexes by Homer proteins.

The number of neurotransmitter receptors in the postsynaptic membrane and their functional coupling to intracellular signalling cascades are important determinants of synaptic strength--and hence potential targets for plasticity related modulation. In this context, Homer/Vesl proteins have gained particular interest for three main reasons: (i) they constitute part of the molecular scaffold at postsynaptic densities of excitatory synapses in the mammalian brain; (ii) they physically link type-I metabotropic glutamate receptors to the postsynaptic density and to inositol 1,4,5-triphosphate receptors in the subsynaptic endoplasmic reticulum; and (iii) Homer-1a, which has been categorized as an immediate early gene isoform, exerts dominant-negative activity, suggesting that it is involved in activity dependent rearrangements at synaptic junctions. Although these fundamental aspects have been reviewed previously by Xiao et al., this review will address primarily more recent studies on the regulation of Homer 1a expression and on the role of Homer/Vesl proteins in spine morphogenesis and receptor targeting and signalling.

Mutation ofDrosophila homerDisrupts Control of Locomotor Activity and Behavioral Plasticity

Homer proteins have been proposed to play a role in synaptogenesis, synapse function, receptor trafficking, and axon pathfinding. Here we report the isolation and characterization of the Drosophila gene homer, the single Homer-related gene in fly. Using anti-Homer antibody we show that Homer is expressed in a broad range of tissues but is highly enriched in the CNS. Similarly to its mammalian counterpart, the Drosophila Homer localizes to the dendrites and the endoplasmic reticulum (ER). This subcellular distribution is dependent on an intact Enabled/Vasp homology 1 domain, suggesting that Homer must bind to one or more of its partners for proper localization. We have created a mutation of homer and show that flies homozygous for this mutation are viable and show coordinated locomotion, suggesting that Homer is not essential for basic neurotransmission. However, we found that homer mutants display defects in behavioral plasticity and the control of locomotor activity. Our results argue that in the CNS, Homer-related proteins operate in the ER and in dendrites to regulate the development and function of neural networks underlying locomotor control and behavioral plasticity.

Potential role of Homer-2a on cutaneous vascular anomaly.

Homer protein was identified based on its rapid induction in rat hippocampal granule cell neurons following excitatory synaptic activity. Although the presence of the Homer gene in the peripheral tissues has been observed in previous reports, the physiological function of the Homer protein in these tissues has not been noted. In this experiment, a Homer-2a cDNA fragment was successfully amplified by RTPCR in the involuting phase of human hemangioma but not in the human vascular malformation and normal vessel. After isolation of full Homer cDNA in a mouse liver cDNA library, E1-deleted recombinant adenovirus expressing the Homer protein (Adv.CMV.mHomer-2a) was constructed to determine its physiological function in peripheral tissues. Adv.CMV.mHomer2a, but not Adv.CMV.LacZ (recombinant adenovirus expressing Beta-galactosidase), strongly inhibited the growth rate of HUVECs (human umbilical vein endothelial cells) probably via inducing apoptosis determined by acridine orange/ethidium bromide (AO/EB) staining methods. This study suggests that the Homer gene is present in human specimens in the involuting phase of hemangioma, and it might be involved in the growth control.

Specificity in signaling and modulators: the Homers

The literature on signal transduction is very confusing. Besides the use of misnomers such as ‘crosstalk’, it can give the impression that all extracellular signals activate all cascades. In fact, in a given cell type at a given stage, only a few signals are active, and their effects are very specific. Among the various factors that confer this specificity, intracellular targeting of the proteins involved, and the cell-specific complement of ‘modulators’ of the cascade, are important. We call modulators proteins or other factors that modulate the level of activity of a cascade without belonging to its direct causal sequence. This is well illustrated by recent work from Bockaert's group on the modulator Homer proteins of the seven-transmembrane metabotropic glutamate receptors mGlu R1 and mGlu R5 [1,2].

Synaptic Activity-Induced Conversion of Intronic to Exonic Sequence in Homer 1 Immediate Early Gene Expression

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.