Coupling of mGluR/Homer and PSD-95 Complexes by the Shank Family of Postsynaptic Density Proteins

Abstract

Shank is a recently described family of postsynaptic proteins that function as part of the NMDA receptor-associated PSD-95 complex (Naisbitt et al., 1999 [this issue of Neuron]). Here, we report that Shank proteins also bind to Homer. Homer proteins form multivalent complexes that bind proline-rich motifs in group 1 metabotropic glutamate receptors and inositol trisphosphate receptors, thereby coupling these receptors in a signaling complex. A single Homer-binding site is identified in Shank, and Shank and Homer coimmunoprecipitate from brain and colocalize at postsynaptic densities. Moreover, Shank clusters mGluR5 in heterologous cells in the presence of Homer and mediates the coclustering of Homer with PSD-95/GKAP. Thus, Shank may cross-link Homer and PSD-95 complexes in the PSD and play a role in the signaling mechanisms of both mGluRs and NMDA receptors.

NMDA-induced potentiation of mGluR5 is mediated by activation of protein phosphatase 2B/calcineurin

“…Furthermore, mGluR5 is physically connected to other proteins in the post-synaptic density via the interacting proteins Homer and Shank Tu et al, 1999). Therefore, we hypothesized that mGluR5 and calcineurin might be connected as components of a signaling complex.…”

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]…”

“…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].…”

“…Thus, the effects of Homer1 deletion upon basal glutamate content can be dissociable from effects upon Group1 mGluR function/expression. Homers regulate the plasma membrane trafficking of NMDA receptors via interactions with a trimeric Shank-GKAP-PSD95 complex that binds to NR2 subunits of the NMDA receptor [138,139,151]. While neither deletion of Homer1 nor Homer2 alters total NMDA receptor subunit expression within the NAC or PFC (Table 3) [34,176], Homer2 deletion reduces the NAC plasma membrane expression of NR2a and NR2b NMDA receptor subunits in vivo [38].…”

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).…”