Homer Binds a Novel Proline-Rich Motif and Links Group 1 Metabotropic Glutamate Receptors with IP3 Receptors

Abstract

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.

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…The EVH1 domain exhibits a high degree of similarity across Homer isoforms and is essential for Homer interactions with a proline-rich sequence (PPSPF) displayed by proteins regulating drug-induced alterations in neuronal morphology, synaptic architecture, and glutamate receptor signaling/intracellular calcium dynamics. Of particular relevance to drug-induced neuroplasticity [e.g., 20,73,74,[78][79][80][81][82][89][90][91][92][93][94][95][96][97][98][99][100][123][124][125][126][127][128][129][130], these proteins include the mGluR1a and mGluR5 subtypes of Group 1 metabotropic glutamate receptors (mGluRs) [34,102,104,107,[131][132][133][134][135][136][137], the NMDA glutamate receptor scaffolding protein Shank [38,132,138,139], the inositol-1,4,5-triphosphate (IP3) receptor, a down-stream mediator of Group1 mGluR signaling [133,[140]…”

“…Exons 6-10 encode the carboxy-tail of the majority of Homer proteins that consists of a coiled-coil (CC) domain, 2 leucine zipper motifs and encode also the 3′ UTR [104,105,107]. Homer proteins multimerize through CC/ leucine zipper motif interactions [104,105,107,133,143,144] and a recent elucidation of the quaternary structure of Homers indicate that these proteins form tetramers with each monomer oriented in parallel [143]. The tetrameric structure of Homer oligomers confers slower turnover rates and greater efficiency of localization to dendritic spines [143].…”

“…Originally hypothesized to serve as a protein scaffold that facilitated intracellular signaling through Group1 mGluRs and calcium-related interactions between these receptors and ionotropic NMDA receptors [e.g., 102,104,133,139], it is now clear that Homer proteins function to regulate many aspects of the functional architecture of glutamatergic synapses. As discussed above, Homers interact via their EVH1 domains with a wide variety of proteins and thus, function not only to scaffold receptors and ion channels on the plasma membrane to the cytoskeleton and intracellular signaling complexes, but also to regulate the function of plasma membrane ion channels and intracellular messenger systems that impact cellular signaling and cell excitability [c.f., [145][146][147][148][149].…”

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

“…Both long and short Homer isoforms interact through an Ena/VASP1 homology (EVH1) domain with a long proline-rich motif located on Group 1 metabotropic glutamate receptors (mGluRs), inositol-1,4,5-triphosphate (IP3) and ryanodine receptors, TRP cation channels and Shank (Brakeman et al, 1997;Hwang et al, 2003;Kammermeier et al, 2000;Kato et al, 1998;Tu et al, 1998Tu et al, , 1999Xiao et al, 1998;Yuan et al, 2003). Long Homer isoforms contain a coiled-coil (CC) domain at their Cterminus that enables the cell membrane localization and clustering of glutamate receptors and proteins involved in their intracellular signaling cascades (Abe et al, 2003;Naisbitt et al, 1999;Rong et al, 2003;Shiraishi et al, 2003a, b).…”

Synaptic concentration of type‐I adenylyl cyclase in cerebellar neurons

“…A large body of evidence has demonstrated that neurotransmitter receptors (Sheng and Pak 1999) and molecules involved in the second messenger system (Chen et al 1998;Kim et al 1998;Tu et al 1998;Wu and Cline 1998) are targeted to specific subcellular domains. In the cAMP signal transduction pathway, PKA was found to be targeted to glutamate receptors and synapses (Carr et al 1992;Colledge et al 2000).…”