Dataset Information

PSD-95 regulates D1 dopamine receptor resensitization, but not receptor-mediated Gs-protein activation.

ABSTRACT: The present study aims to define the role of postsynaptic density (PSD)-95 in the regulation of dopamine (DA) receptor function. We found that PSD-95 physically associates with either D(1) or D(2) DA receptors in co-transfected HEK-293 cells. Stimulation of DA receptors altered the association between D(1) receptor and PSD-95 in a time-dependent manner. Functional assays indicated that PSD-95 co-expression did not affect D(1) receptor-stimulated cAMP production, Gs-protein activation or receptor desensitization. However, PSD-95 accelerated the recovery of internalized membrane receptors by promoting receptor recycling, thus resulting in enhanced resensitization of internalized D(1) receptors. Our results provide a novel mechanism for regulating DA receptor recycling that may play an important role in postsynaptic DA functional modulation and synaptic neuroplasticity.

SUBMITTER: Sun P

PROVIDER: S-EPMC5800406 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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PSD-95 regulates D1 dopamine receptor resensitization, but not receptor-mediated Gs-protein activation.

Sun Peihua P Wang Jingru J Gu Weihua W Cheng Wei W Jin Guo-zhang GZ Friedman Eitan E Zheng Jie J Zhen Xuechu X

Cell research 20090501 5

The present study aims to define the role of postsynaptic density (PSD)-95 in the regulation of dopamine (DA) receptor function. We found that PSD-95 physically associates with either D(1) or D(2) DA receptors in co-transfected HEK-293 cells. Stimulation of DA receptors altered the association between D(1) receptor and PSD-95 in a time-dependent manner. Functional assays indicated that PSD-95 co-expression did not affect D(1) receptor-stimulated cAMP production, Gs-protein activation or receptor ...[more]

PMID: 19274064

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Project description:In neuronal synapses, PDZ domains [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] of PSD-95 proteins interact with C termini of NMDA receptor [NMDAR (NR)] subunits, linking them to downstream neurotoxic signaling molecules. Perturbing NMDAR/PSD-95 interactions with a Tat peptide comprising the nine C-terminal residues of the NR2B subunit (Tat-NR2B9c) reduces neurons' vulnerability to excitotoxicity and ischemia. However, NR subunit C termini may bind many of >240 cellular PDZs, any of which could mediate neurotoxic signaling independently of PSD-95. Here, we performed a proteomic and biochemical analysis of the interactions of all known human PDZs with synaptic signaling proteins including NR1, NR2A-NR2D, and neuronal nitric oxide synthase (nNOS). Tat-NR2B9c, whose interactions define PDZs involved in neurotoxic signaling, was also used. NR2A-NR2D subunits and Tat-NR2B9c had similar, highly specific, PDZ protein interactions, of which the strongest were with the PSD-95 family members (PSD-95, PSD-93, SAP97, and SAP102) and Tax interaction protein 1 (TIP1). The PSD-95 PDZ2 domain bound NR2A-NR2C subunits most strongly (EC50, approximately 1 microM), and fusing the NR2B C terminus to Tat enhanced its affinity for PSD-95 PDZ2 by >100-fold (EC50, approximately 7 nM). IC50 values for Tat-NR2B9c inhibiting NR2A-NR2C/PSD-95 interactions (approximately 1-10 microM) and nNOS/PSD-95 interactions (200 nM) confirmed the feasibility of such inhibition. To determine which of the PDZ interactions of Tat-NR2B9c mediate neuroprotection, one of PSD-95, PSD-93, SAP97, SAP102, TIP1, or nNOS expression was inhibited in cortical neurons exposed to NMDA toxicity. Only neurons lacking PSD-95 or nNOS but not PSD-93, SAP97, SAP102, or TIP1 exhibited reduced excitotoxic vulnerability. Thus, despite the ubiquitousness of PDZ domain-containing proteins, PSD-95 and nNOS above any other PDZ proteins are keys in effecting NMDAR-dependent excitotoxicity. Consequently, PSD-95 inhibition may constitute a highly specific strategy for treating excitotoxic disorders.

Dataset Information

PSD-95 regulates D1 dopamine receptor resensitization, but not receptor-mediated Gs-protein activation.

Publications

PSD-95 regulates D1 dopamine receptor resensitization, but not receptor-mediated Gs-protein activation.

Similar Datasets

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