The DREAM Protein Negatively Regulates the NMDA Receptor through Interaction with the NR1 Subunit

Abstract

Glutamate-induced excitotoxicity has been implicated in the etiology of stroke, epilepsy, and neurodegenerative diseases. NMDA receptors (NMDARs) play a pivotal role in excitotoxic injury; however, clinical trials testing NMDAR antagonists as neuroprotectants have been discouraging. The development of novel neuroprotectant molecules is being vigorously pursued. Here, we report that downstream regulatory element antagonist modulator (DREAM) significantly inhibits surface expression of NMDARs and NMDAR-mediated current. Overexpression of DREAM showed neuroprotection against excitotoxic neuronal injury, whereas knockdown of DREAM enhanced NMDA-induced toxicity. DREAM could directly bind to the C0 domain of the NR1 subunit. Although DREAM contains multiple binding sites for the NR1 subunit, residues 21-40 of the N terminus are the main binding site for the NR1 subunit. Thus, 21-40 residues might relieve the autoinhibition conferred by residues 1-50 and derepress the DREAM core domain by a competitive mechanism. Intriguingly, the cell-permeable TAT-21-40 peptide, constructed according to the critical binding site of DREAM to the NR1 subunit, inhibits NMDARmediated currents in primary cultured hippocampal neurons and has a neuroprotective effect on in vitro neuronal excitotoxic injury and in vivo ischemic brain damage. Moreover, both pretreatment and posttreatment of TAT-21-40 is effective against excitotoxicity. In summary, this work reveals a novel, negative regulator of NMDARs and provides an attractive candidate for the treatment of excitotoxicity-related disease.

The Potassium Channel Interacting Protein 3 (DREAM/KChIP3) Heterodimerizes with and Regulates Calmodulin Function

“…DREAM/KChIP3 also binds to the amino-terminal portion of Ca 2ϩ -activated Kv4 potassium channels, which are highly expressed in the brain and heart and contribute to the transient, voltage-dependent potassium ion currents (A-currents) in the nervous system and the transient outward currents in the heart (15,16). DREAM also modulates signaling of the N-methyl-D-aspartate membrane receptor (17 …”

DREAM regulates insulin promoter activity through newly identified DRE element

“…The repression of gene transcription by DREAM-DRE promoter element interaction is abolished when intracellular free Ca 2+ is elevated [1,2]. Using transgenic mice (TgDREAM) overexpressing a Ca 2+ -and cAMP-insensitive DREAM mutant it was found that NMDA receptor-mediated synaptic transmission and plasticity was impaired in TgDREAM mice [27,28]. Zaidi et al [29] have found that calsenilin traslocates from the cytoplasm to the nucleus when cells were treated with pharmacological agents that directly manipulate the levels of intracellular calcium (caffeine and the calcium ionophore A23187), suggesting that the increased levels of calsenilin in the nucleus are mediated by changes in the intracellular calcium concentration [29].…”

Protein Kinase D1-Dependent Phosphorylation of Dopamine D1 Receptor Regulates Cocaine-Induced Behavioral Responses

“…S421A mutation significantly reduced surface D1R (t 2 ¼ 5.8, po0.05), whereas no significant difference of the total levels of D1R and S421A-D1R was detected (Figure 2b). Tat-mediated intracellular delivery of functional peptides is an effective intervention method that has been proved by us and others (Futaki, 2005;Ji et al, 2006;Zhang et al, 2010). Thus, we constructed a Tat-S421 peptide (Figure 2c, top) to competitively inhibit the phosphorylation of D1R on S421.…”