Homer 1c Research Articles

Homer signaling pathways as effective therapeutic targets for ischemic and traumatic brain injuries and retinal lesions.

Ischemic and traumatic insults to the central nervous system account for most serious acute and fatal brain injuries and are usually characterized by primary and secondary damage. Secondary damage presents the greatest challenge for medical staff; however, there are currently few effective therapeutic targets for secondary damage. Homer proteins are postsynaptic scaffolding proteins that have been implicated in ischemic and traumatic insults to the central nervous system. Homer signaling can exert either positive or negative effects during such insults, depending on the specific subtype of Homer protein. Homer 1b/c couples with other proteins to form postsynaptic densities, which form the basis of synaptic transmission, while Homer1a expression can be induced by harmful external factors. Homer 1c is used as a unique biomarker to reveal alterations in synaptic connectivity before and during the early stages of apoptosis in retinal ganglion cells, mediated or affected by extracellular or intracellular signaling or cytoskeletal processes. This review summarizes the structural features, related signaling pathways, and diverse roles of Homer proteins in physiological and pathological processes. Upregulating Homer1a or downregulating Homer1b/c may play a neuroprotective role in secondary brain injuries. Homer also plays an important role in the formation of photoreceptor synapses. These findings confirm the neuroprotective effects of Homer, and support the future design of therapeutic drug targets or gene therapies for ischemic and traumatic brain injuries and retinal disorders based on Homer proteins.

Homer 1a Induces Calcium Channel Activation, but Does Not Change Their Properties in A431 Cells.

Store-operated channels activated in response to intracellular calcium store depletion represent the main pathway of calcium entry from the extracellular space in nonelectroexcitable cells. Adapter proteins organize the components of this system into integral complex. We studied the influence of adapter proteins of the Homer family on endogenous store-operated calcium Imin channels in A431 cells. Monomeric Homer 1a proteins increase activity of Imin channels, but did not modulate their electrophysiological properties. Recombinant Homer 1c protein did not block the induced calcium currents.

Differential up-regulation of Vesl-1/Homer 1 protein isoforms associated with decline in visual performance in a preclinical glaucoma model.

Glaucoma is a multifactorial progressive ocular pathology, clinically presenting with damage to the retina and optic nerve, ultimately leading to blindness. Retinal ganglion cell loss in glaucoma ultimately results in vision loss. Vesl/Homer proteins are scaffolding proteins that are critical for maintaining synaptic integrity by clustering, organizing and functionally regulating synaptic proteins. Current anti-glaucoma therapies target IOP as the sole modifiable clinical parameters. Long-term pharmacotherapy and surgical treatment do not prevent gradual visual field loss as the disease progresses, highlighting the need for new complementary, alternative and comprehensive treatment approaches. Vesl/Homer expression was measured in the retinae of DBA/2J mice, a preclinical genetic glaucoma model with spontaneous mutations resulting in a phenotype reminiscent of chronic human pigmentary glaucoma. Vesl/Homer proteins were differentially expressed in the aged, glaucomatous DBA/2J retina, both at the transcriptional and translational level. Immunoreactivity for the long Vesl-1L/Homer 1c isoform, but not of the immediate early gene product Vesl-1S/Homer 1a was increased in the synaptic layers of the retina. This increased protein level of Vesl-1L/Homer 1c was correlated with phenotypes of increased disease severity and a decrease in visual performance. The increased expression of Vesl-1L/Homer 1c in the glaucomatous retina likely results in increased intracellular Ca(2+) release through enhancement of synaptic coupling. The ensuing Ca(2+) toxicity may thus activate neurodegenerative pathways and lead to the progressive loss of synaptic function in glaucoma. Our data suggest that higher levels of Vesl-1L/Homer 1c generate a more severe disease phenotype and may represent a viable target for therapy development.

The uncoupling of synaptic protein homer 1c from target proteins activates store-operated calcium entry in a neurotransmitter-like manner in human neuroblastoma cells

The uncoupling of synaptic protein homer 1c from target proteins activates store-operated calcium entry in a neurotransmitter-like manner in human neuroblastoma cells

Homer proteins accelerate Ca2+ clearance mediated by the plasma membrane Ca2+ pump in hippocampal neurons

The plasma membrane Ca2+ ATPase (PMCA) is responsible for maintaining basal intracellular Ca2+ concentration ([Ca2+]i) and returning small increases in [Ca2+]i back to resting levels. The carboxyl terminus of some PMCA splice variants bind Homer proteins; how binding affects PMCA function is unknown. Here, we examined the effects of altered expression of Homer proteins on PMCA-mediated Ca2+ clearance from rat hippocampal neurons in culture. The kinetics of PMCA-mediated recovery from the [Ca2+]i increase evoked by a brief train of action potentials was determined in the soma of single neurons using indo-1-based photometry. Exogenous expression of Homer 1a, Homer 1c or Homer 2a did not affect PMCA function. However, shRNA mediated knockdown of Homer 1 slowed PMCA mediated Ca2+ clearance by 28% relative to cells expressing non-silencing shRNA. The slowed recovery rate in cells expressing Homer 1 shRNA was reversed by expression of a short Homer 2 truncation mutant. These results indicate that constitutively expressed Homer proteins tonically stimulate PMCA function in hippocampal neurons. We propose a model in which binding of short or long Homer proteins to the carboxyl terminus of the PMCA stimulates Ca2+ clearance rate. PMCA-mediated Ca2+ clearance may be stimulated following incorporation of the pump into Homer organized signaling domains and following induction of the Homer 1a immediate early gene.

Scaffolding protein Homer 1c mediates hypertrophic responses downstream of Gq in cardiomyocytes

Activation of the heterotrimeric G protein, Gq, causes cardiomyocyte hypertrophy in vivo and in cell models. Responses to activated Gq in cardiomyocytes are mediated exclusively by phospholipase Cβ1b (PLCβ1b), because it localizes at the sarcolemma by binding to Shank3, a high-molecular-weight (MW) scaffolding protein. Shank3 can bind to the Homer family of low-MW scaffolding proteins that fine tune Ca(2+) signaling by facilitating crosstalk between Ca(2+) channels at the cell surface with those on intracellular Ca(2+) stores. Activation of α(1)-adrenergic receptors, expression of constitutively active Gαq (GαqQL), or PLCβ1b initiated cardiomyocyte hypertrophy and increased Homer 1c mRNA expression, by 1.6 ± 0.18-, 1.9 ± 0.17-, and 1.5 ± 0.07-fold, respectively (means ± se, 6 independent experiments, P<0.05). Expression of Homer 1c induced an increase in cardiomyocyte area from 853 ± 27 to 1146 ± 31 μm(2) (P<0.05); furthermore, expression of dominant-negative Homer (Homer 1a) reversed the increase in cell size caused by α(1)-adrenergic agonist or PLCβ1b treatment (1503±48 to 996±28 and 1626±48 to 828±31 μm(2), respectively, P<0.05). Homer proteins were localized near the sarcolemma, associated with Shank3 and phospholipase Cβ1b. We conclude that Gq-mediated hypertrophy involves activation of PLCβ1b scaffolded onto a Shank3/Homer complex. Signaling downstream of Homer 1c is necessary and sufficient for Gq-initiated hypertrophy.

Homer regulation of native plasma membrane calcium channels in A431 cells

Homers are adapter proteins that play a significant role in the organization of calcium signaling protein complexes. Previous functional studies linked Homer proteins to calcium influx in nonexcitable cells. These studies utilized calcium imaging or whole-cell current recordings. Because of limited resolution of these methods, an identity of Homer-modulated ion channels remained unclear. There are several types of plasma membrane calcium influx channels in A431 cells. In the present study, we demonstrated that Homer dissociation resulted in specific activation of I min channels but not of I max channels in inside-out patches taken from A431 cells. In contrast, inositol 1,4,5-trisphosphate activated both I min and I max channels in inside-out patches. Short (1a) and long (1c) forms of Homer had different effects on I min channel activity. Homer 1a but not Homer 1c activated I min in the patches. This study indicates that I min channels are specifically regulated by Homer proteins in A431 cells.

The role of homer family adaptor proteins in regulation of store-operated calcium influx in A431 cells

332 The major pathways for Ca 2+ influx in nonexcitable cells are store-operated channels (SOC). SOCs are activated by depletion of intracellular calcium stores. In the previous studies we used patch-clamp electrophysiology to describe the properties of store-operated channels I min in human carcinoma A431 cell lines. I min are gated by direct protein-protein interaction with inositol-1,4,5-trisphosphate receptor type 1 (IP 3 R1). We supposed that this interaction might be facilitated by scaffold proteins of Homer family. Homer family proteins specifically bind to unique PPXXF sequence in IP 3 R and in some other proteins. Several isoforms of Homer proteins exist. Homer 1c isoforms have coilcoiled domain, which mediate homooligomerization. That is why Homer 1c oligomers can form macromolecular complexes with partner proteins. Homer 1a isoform lacking coil-coiled domain can disrupt macromolecular complexes of Homer 1c and its partner proteins. The aim of this study was to determine the role of Homer protein in activation of store-operated channels. We applied the Gst-Homer recombinant protein (concentration 100 nM) to inside-out patches excised from A431 cells using 105 mM Ba 2+ in the pipette as a current carrier. Application of Gst-Homer 1c to the cytosolic surface of the patch did not activate channels. Addition of GST Homer 1a to the same patch resulted in an activation of I min channels.

A neurotoxic dose of methamphetamine induces gene expression of Homer 1a, but not Homer 1b or 1c, in the striatum and nucleus accumbens

Homer proteins, which regulate the signaling pathway of metabotropic glutamate receptors, may contribute to the glutamatergic modulation of dopamine neurons in the basal ganglia. This study examined whether the induction of Homer 1 genes is or not associated with the methamphetamine-induced dopaminergic neurotoxicity in the discrete brain regions of rats. Basal levels of Homer 1a and 1c mRNAs in the forebrain regions were higher than those in the substantia nigra, whereas Homer 1b mRNA levels were higher in the substantia nigra than those in the forebrain regions examined. A neurotoxic dose (40 mg/kg, i.p.) of methamphetamine increased the mRNA and protein levels of Homer 1a in the striatum and nucleus accumbens, but not in the medial prefrontal cortex or the substantia nigra. Both Homer 1b and 1c mRNAs were not affected in any brain regions examined. These results suggest that the induction of Homer 1a gene may be involved at least in part in the methamphetamine-induced dopaminergic neurotoxicity, possibly through the glutamate-dopaminergic interaction.

Homer proteins control neuronal differentiation through IP 3 receptor signaling

Neurons expand, sustain or prune their dendritic trees during ontogenesis [Cline, H.T. (2001). Dendritic arbor development and synaptogenesis. Curr. Opin. Neurobiol. 11, 118–126; Wong, W.T. and Wong, R.O.L. (2000) Rapid dendritic movements during synapse formation and rearrangement. Curr. Opin. Neurobiol. 10, 118–124] which critically depends on neuronal activity [Wong, W.T., Faulkner-Jones, B.E., Sanes, J.R. and Wong, R.O.L. (2000) Rapid dendritic remodeling in the developing retina: dependence on neurotransmission and reciprocal regulation by Rac and Rho. J. Neurosci. 20, 5024–5036; Li, Z., Van Aelst, L. and Cline, H.T. (2000) Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo. Nat. Neurosci. 3, 217–225; Wong, W.T. and Wong, R.O.L. (2001) Changing specificity of neurotransmitter regulation of rapid dendritic remodeling during synaptogenesis. Nat. Neurosci. 4, 351–352.] and sub-cellular Ca 2+ signals [Lohmann, C., Myhr, K.L. and Wong, R.O. (2002) Transmitter-evoked local calcium release stabilizes developing dendrites, Nature 418, 177–181.]. The role of synaptic clustering proteins connecting both processes is unclear. Here, we show that expression levels of Vesl-1/Homer 1 isoforms critically control properties of Ca 2+ release from intracellular stores and dendritic morphology of CNS neurons. Vesl-1L/Homer 1c, an isoform with a functional WH1 and coiled-coil domain, but not isoforms missing these features were capable of potentiating intracellular calcium signaling activity indicating that such regulatory interactions function as a general paradigm in cellular differentiation and are subject to changes in expression levels of Vesl/Homer isoforms.

Essential Contribution of the Ligand-Binding βB/βC Loop of PDZ1 and PDZ2 in the Regulation of Postsynaptic Clustering, Scaffolding, and Localization of Postsynaptic Density-95

Postsynaptic density-95 (PSD-95), a PSD-95/Discs large/zona occludens-1 (PDZ) domain-containing scaffold protein, clusters many signaling molecules near NMDA-type glutamate receptors in the postsynaptic densities. Although the synaptic localization of PSD-95 requires palmitoylation of two cysteines at the N terminus and the presence of at least one PDZ domain, how the clustering of PSD-95 is initiated and regulated remains essentially unknown. To address this issue, we examined PSD-95 clustering in primary cultured hippocampal neurons expressing full-length PSD-95 mutant proteins lacking the ligand-binding ability of PDZ1, PDZ2, and/or PDZ3. The formation of either excitatory or inhibitory synapses was unaffected. Combinations of individual mutations, however, significantly reduced the PSD-95 clustering index, in an approximately additive manner. The sensitivity to 2-bromo-palmitate and latrunculin A, reagents known to affect PSD-95 turnover, was also augmented. Furthermore, the synaptic recruitment of a PSD-95 ligand, synaptic GTPase-activating protein (synGAP), was significantly impaired, whereas the clustering of other scaffolding proteins, such as Homer 1c, Shank/Synamon, and PSD-93/Chapsin-110 was spared. Intriguingly, overexpression of the PSD-95 PDZ1/2/3 mutants caused the PSD-95 clusters to localize away from the dendritic shaft, resulting in the formation of elongated spines, in an inverse correlation with the overall PDZ-ligand affinity. Expression of a mutant synGAP lacking the PDZ-binding motif replicated both the clustering and spine morphology phenotypes. In conclusion, the ligand-binding affinity of the PDZ domains of PSD-95, contributed in part via its interaction with the C-terminal end of synGAP, plays a critical role in titrating the synaptic clustering of PSD-95 and controlling its tight association with the PSD scaffold, thereby affecting synapse maturation.

AAV-mediated hippocampal expression of short and long Homer 1 proteins differentially affect cognition and seizure activity in adult rats

Homer proteins mediate molecular rearrangements leading to changes in spine morphology. This points to a role of Homer in learning and memory. Homer 1c features both the ligand binding domain and a coiled–coiled domain for self-multimerization. Homer 1a lacks the coiled–coiled domain. Here, we report a new isoform which we termed 1g, lacking the Homer ligand binding domain. We dissected the functional roles of the individual Homer 1 domains, encoded by Homer 1a, 1c, and 1g, in vivo. Recombinant adeno-associated virus (AAV)-mediated overexpression of these forms in the hippocampus of adult rats has opposing effects on learning behavior. Increased levels of Homer 1a impaired hippocampal-dependent memory, while Homer 1g and 1c slightly enhanced memory performance. Homer 1g induced anxiety. Moreover, AAV-Homer 1a animals showed attenuation of electrographic seizures in a model of status epilepticus. These results suggest that Homer 1 proteins play an active role in behavioral plasticity.

Topology of Homer 1c and Homer 1a in C 2C 12 myotubes and transgenic skeletal muscle fibers

mRNA transcripts for Homer 1a and Homer 1c have been detected in skeletal muscle [Biochem. Biophys. Res. Commun. 279 (2000) 348]. Here, the subcellular distribution of recombinant HA1-tagged Homer 1c and HA1-tagged Homer 1a was investigated in C 2C 12 myotubes and in transgenic skeletal muscle fibers of the adult rat by epifluorescent and confocal microscopy. In C 2C 12 myotubes, Homer 1a was homogeneously localized in the cytosol and also labeled some nuclei whereas Homer 1c displayed a diffuse reticular/punctuate pattern in the cytosol with scattered punctuate labeling around nuclei; no co-localization was observed with the ryanodine receptor/Ca 2+ release channel (RYR1). The subcellular localization of the Homer 1 isoforms was markedly different in transgenic muscle fibers: Homer 1c was diffusely distributed at the I band and enlightened the Z line, whereas Homer 1a labeled both the I band and the A band with distinct reinforcement of the H line; neither Homer 1c nor Homer 1a co-localized with either calsequestrin or RYR1, two sarcoplasmic reticulum markers. Our findings are discussed in relation to reported effects of Homer 1 isoforms on RYR1 function.

Estrogen protects the inner retina from apoptosis and ischemia-induced loss of Vesl-1L/Homer 1c immunoreactive synaptic connections.

Protective effects of estrogen on nerve cells including retinal neurons have been described previously. However, subcellular effects on synaptic connectivity in mild ischemia more closely resembling ischemic conditions found in diabetic or sickle cell retinopathy and stenosis of the carotid artery have not been identified. The present study quantitatively analyzed effects of estrogen administration on synaptic connections of neurons in the ganglion cell layer (GCL) of the retina. Staining of Vesl-1L/Homer 1c (V-1L) immunoreactivity and TUNEL cytochemistry were used to quantify neuroprotective effects at the synaptic level in a model of mild retinal ischemia induced by temporary middle cerebral artery occlusion in the adult rat. V-1L immunoreactivity was found in both synaptic layers, postsynaptic to glutamatergic ribbon synapses. Mild retinal ischemia led to a significantly higher percentage reduction in the number of V-1L-positive synapses in the inner plexiform layer (IPL) compared with the percentage of TUNEL-positive apoptotic neurons in the GCL. Estrogen prevented ischemia-induced loss of V-1L-immunoreactive synapses in the IPL and apoptosis of cells in the GCL. Immunoreactivity for V-1L can be used as a synaptic marker for early changes before more severe neurodegenerative events. The present results suggest that estrogen protects neurons in the GCL including RGCs from both apoptosis and early changes in synaptic connections associated with ischemia and potentially preceding apoptosis.

Effects of coexpression with Homer isoforms on the function of metabotropic glutamate receptor 1α

We previously showed that the metabotropic glutamate receptor 1α (mGluR1α) has a sensitivity to extracellular polyvalent cations such as Ca 2+ and Gd 3+ as well as glutamate. Here we show that mGluR1α-mediated responses to these ligands are modulated by the scaffold protein Homer. When HEK293 cells were transiently cotransfected with Homer 1c and mGluR1α, 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 mGluR1α 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 mGluR1α were decreased significantly in mGluR1α P1147E mutant which lacks the affinity to Homer, showing that the effects were mediated by binding to mGluR1α. Taken together, the binding of Homer 1c to mGluR1α 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.

Heterodimerization of Calcium Sensing Receptors with Metabotropic Glutamate Receptors in Neurons

Calcium sensing (CaR) and Group I metabotropic glutamate receptors exhibit overlapping expression patterns in brain, and share common signal transduction pathways. To determine whether CaR and Group I metabotropic glutamate receptors (mGluRs) (mGluR1alpha and mGluR5) can form heterodimers, we immunoprecipitated CaR from bovine brain and observed co-precipitation of mGluR1alpha. CaR and mGluR1alpha co-localize in hippocampal and cerebellar neurons, but are expressed separately in other brain regions. In vitro transfection studies in HEK-293 cells established the specificity and disulfide-linked nature of the CaR:mGluR1alpha (CaR:mGluR5) interactions. CaR:mGluR1alpha (CaR:mGluR5) heterodimers exhibit altered trafficking via Homer 1c when compared with CaR:CaR homodimers. CaR becomes sensitive to glutamate-mediated internalization when present in CaR:mGluR1alpha heterodimers. These results demonstrate cross-family covalent heterodimerization of CaR with Group I mGluRs, and increase the potential role(s) for CaR in modulating neuronal function.

Characterization of a Metabotropic Glutamate Receptor Type 5-Green Fluorescent Protein Chimera (mGluR5–GFP): Pharmacology, Surface Expression, and Differential Effects of Homer-1a and Homer-1c

Metabotropic glutamate receptor 5 (mGluR5) can modulate synaptic transmission by increasing intracellular Ca2+ and it plays a role in several forms of synaptic plasticity. We have constructed a fusion of human mGluR5 and green fluorescent protein (mGluR5–GFP). Expression of mGluR5–GFP in clonal cell lines yielded a functional fluorescent receptor with pharmacological profiles similar to wild-type mGluR5. mGluR5–GFP coimmunoprecipitated with Homer-1c, indicating that addition of GFP to the C-terminal did not prevent Homer binding. Coexpression of wild-type mGluR5 or mGluR5–GFP with Homer 1c, but not Homer-1a, resulted in reduced receptor surface localization and the formation of intracellular clusters. Neither Homer-1a nor Homer-1c had any effect on mGluR1 or mGluR1–GFP distribution. mGluR5–GFP expressed alone or in combination with Homer-1a formed dimers in HEK cells. Coexpression with Homer-1c, however, prevented mGluR5–GFP dimerization. Neither Homer altered the agonist profiles of mGluR5 or mGluR5–GFP. These data indicate that the functional expression of mGluR5 is regulated by Homer-1c and demonstrate that mGluR5–GFP provides a useful tool to study the molecular pharmacology and cell biology of mGluRs in real-time.

Homer in Axon Pathfinding

Homer family proteins function as intracellular adapter proteins and are composed of well-characterized protein domains. In mammals, Homer1 is alternatively spliced to produce three different proteins: Homer1a, 1b, and 1c. All three isoforms have an EVH1 (enabled VASP homology 1) domain that allows Homer proteins to associate with other proteins that contain specific proline-rich motifs. However, only the longer forms of Homer (1b and 1c) have a COOH-terminal coiled-coil domain that allows Homer proteins to dimerize. Foa et al. expressed Homer1 proteins in Xenopus and determined that Homer1 proteins have an essential role in axon pathfinding. Overexpression of vaccinia virus-transduced Homer1a led to the development of aberrant axonal projections and incorrect pathfinding in Xenopus optical tecta. Expression of a Homer1a mutant that prevented protein binding did not interfere with pathfinding, suggesting that Homer1a was interfering possibly with the ability of Homer1b/1c to cross-link proteins important for pathfinding. Overexpression of a Homer1c mutant that could dimerize but not bind other proteins also resulted in defective pathfinding, probably as a result of being unable to recruit and cross-link essential proteins necessary for pathfinding. Overexpression of wild-type Homer1c also resulted in defective axonal pathfinding; however, this might be explained by the possibility that high nonphysiological amounts of Homer1c dimerize before binding the critical transmembrane proteins. In this instance, the transmembrane proteins would be occupied and unavailable for cross-linking, thus leading to the outcome of defective axonal pathfinding. L. Foa, I. Rajan, K. Haas, G.-Y. Wu, P. Brakeman, P. Worley, H. Cline, The scaffold protein, Homer1b/c, regulates axon pathfinding in the central nervous system in vivo. Nature Neurosci. 4 , 499-506 (2001). [Online Journal]

Homer in Axon Pathfinding

Homer family proteins function as intracellular adapter proteins and are composed of well-characterized protein domains. In mammals, Homer1 is alternatively spliced to produce three different proteins: Homer1a, 1b, and 1c. All three isoforms have an EVH1 (enabled VASP homology 1) domain that allows Homer proteins to associate with other proteins that contain specific proline-rich motifs. However, only the longer forms of Homer (1b and 1c) have a COOH-terminal coiled-coil domain that allows Homer proteins to dimerize. Foa et al. expressed Homer1 proteins in Xenopus and determined that Homer1 proteins have an essential role in axon pathfinding. Overexpression of vaccinia virus-transduced Homer1a led to the development of aberrant axonal projections and incorrect pathfinding in Xenopus optical tecta. Expression of a Homer1a mutant that prevented protein binding did not interfere with pathfinding, suggesting that Homer1a was interfering possibly with the ability of Homer1b/1c to cross-link proteins important for pathfinding. Overexpression of a Homer1c mutant that could dimerize but not bind other proteins also resulted in defective pathfinding, probably as a result of being unable to recruit and cross-link essential proteins necessary for pathfinding. Overexpression of wild-type Homer1c also resulted in defective axonal pathfinding; however, this might be explained by the possibility that high nonphysiological amounts of Homer1c dimerize before binding the critical transmembrane proteins. In this instance, the transmembrane proteins would be occupied and unavailable for cross-linking, thus leading to the outcome of defective axonal pathfinding. L. Foa, I. Rajan, K. Haas, G.-Y. Wu, P. Brakeman, P. Worley, H. Cline, The scaffold protein, Homer1b/c, regulates axon pathfinding in the central nervous system in vivo. Nature Neurosci. 4, 499-506 (2001).[Online Journal]

Evidence for the Presence of Two Homer 1 Transcripts in Skeletal and Cardiac Muscles

A family of proteins, Homers 1, 2 and 3, involved in activity-dependent control of signal transduction has been recently described in neurons [Xiao, B., Tu, C. J., Petralia, R. S., Yuan, J. P., Doan, A., Breder, C. D., Ruggiero, A., Lanahan, A. A., Wenthold, R. J., and Worley, P. F. (1998) Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of Homer-related, synaptic proteins. Neuron 21, 707–716]. By RT-PCR and RNasePA, mRNAs transcripts for Homer 1a and Homer 1c, but not Homer 1b, are detected in both skeletal and cardiac muscles of the rat. Full-length cloning of Homer 1a and Homer 1c cDNAs has been accomplished: There is no tissue specificity, by comparing skeletal muscle, cardiac muscle and cerebellum, and there are a few species-specific base substitutions, by comparing rat and mouse sequences. The regulatory mechanism exerted via transition of Homer 1 isoform composition may be operative in striated muscles.