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

Tu, Jian Cheng; Xiao, Bo; Naisbitt, Scott; Yuan, Joseph P.; Petralia, Ronald S.; Brakeman, Paul; Doan, Andrew; Aakalu, Vinay K.; Lanahan, Anthony A.; Sheng, Morgan; Worley, Paul F.

doi:10.1016/s0896-6273(00)80810-7

Cited by 979 publications

(805 citation statements)

References 44 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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

Alagarsamy¹,

Saugstad²,

Warren

et al. 2005

Neuropharmacology

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Previous reports have shown that activation of N-methyl-D-aspartate (NMDA) receptors potentiates responses to activation of the group I metabotropic glutamate receptor mGluR5 by reversing PKC-mediated desensitization of this receptor. NMDA-induced reversal of mGluR5 desensitization is dependent on activation of protein phosphatases. However, the specific protein phosphatase involved and the precise mechanism by which NMDA receptor activation reduces mGluR desensitization are not known. We have performed a series of molecular, biochemical, and genetic studies to show that NMDA-induced regulation of mGluR5 is dependent on activation of calcium-dependent protein phosphatase 2B/calcineurin (PP2B/CaN). Furthermore, we report that purified calcineurin directly dephosphorylates the C-terminal tail of mGluR5 at sites that are phosphorylated by PKC. Finally, immunoprecipitation and GST fusion protein pull-down experiments reveal that calcineurin interacts with mGluR5, suggesting that these proteins could be colocalized in a signaling complex. Taken together with previous studies, these data suggest that activation of NMDA receptors leads to activation of calcineurin and that calcineurin modulates mGluR5 function by directly dephosphorylating mGluR5 at PKC sites that are involved in desensitization of this receptor.

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Section: Resultsmentioning

confidence: 99%

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

Alagarsamy¹,

Saugstad²,

Warren

et al. 2005

Neuropharmacology

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“…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]…”

Section: Molecular Aspects Of Homer Proteinsmentioning

confidence: 99%

“…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].…”

Section: Homer Regulation Of Corticoaccumbens Glutamate In Vivomentioning

confidence: 99%

“…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].…”

Section: Homer Regulation Of Corticoaccumbens Glutamate In Vivomentioning

confidence: 99%

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Homers regulate drug-induced neuroplasticity: Implications for addiction

Szumlinski

Ary

Lominac

2008

Biochemical Pharmacology

118

160

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Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

Szumlinski

Abernathy

Oleson

et al. 2005

Neuropsychopharmacol

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Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.

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

Cited by 979 publications

References 44 publications

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

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

Homers regulate drug-induced neuroplasticity: Implications for addiction

Homer Isoforms Differentially Regulate Cocaine-Induced Neuroplasticity

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