Subtype‐Specific Enhancement of NMDA Receptor Currents by Mutant Huntingtin

Chen, Nansheng; Luo, Tao; Wellington, Cheryl L.; Metzler, Martina; McCutcheon, Krista; Hayden, Michael R.; Raymond, Lynn A.

doi:10.1046/j.1471-4159.1999.0721890.x

Cited by 177 publications

(103 citation statements)

References 70 publications

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“…3C), suggesting that activation of both mGluR1/5 and NMDAR is necessary for dopamine/ glutamate-induced apoptosis of YAC128 MSNs in our in vitro HD model. Htt exp specifically facilitates activity of the NR2B subtype of NMDA receptors (Chen et al, 1999;Sun et al, 2001;Zeron et al, 2002Zeron et al, , 2004Song et al, 2003) and InsP 3 R1 (Tang et al, 2003b). The involvements of NR2B subtype of NMDAR and InsP 3 R were also confirmed by specific blocker of NR2B (ifenprodil) and membrane-permeable InsP 3 R blockers (2-APB and enoxaparin) (Fig.…”

Section: Pharmacology Of Dopamine/glutamate-induced Apoptosis Of Hd Msnsmentioning

confidence: 65%

“…1). However, in HD MSNs, mutant Htt exp further potentiates the activity of NR2B NMDAR (Chen et al, 1999;Sun et al, 2001;Zeron et al, 2002Zeron et al, , 2004Song et al, 2003) and InsP 3 R1 (Tang et al, 2003b). Thus, convergence of dopamine and glutamate signaling pathways promotes cytosolic and mitochondrial Ca 2ϩ overload and apoptosis of HD MSNs (Fig.…”

Section: Dopaminergic Signaling and Neurodegeneration Of Hd Msnsmentioning

confidence: 96%

“…Recent results suggested that abnormal Ca 2ϩ signaling may play an important role in HD pathogenesis (Bezprozvanny and Hayden, 2004). It has been demonstrated that Htt exp facilitates activity of the NR2B subtype of NMDA receptors (Chen et al, 1999;Sun et al, 2001;Zeron et al, 2002;Song et al, 2003) and the type 1 inositol 1,4,5-trisphosphate receptors (InsP 3 R1s) (Tang et al, 2003b). Recent studies with the MSN neurons from the yeast artificial chromosome (YAC) transgenic HD mouse models supported the connection between activation of glutamate receptors, Ca 2ϩ overload, and apoptosis of MSNs in HD (Zeron et al, 2004;Tang et al, 2005;Shehadeh et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Dopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease

Tang¹,

Chen²,

Liu³

et al. 2007

J. Neurosci.

188

190

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Huntington's disease (HD) is a neurodegenerative disorder caused by polyglutamine (polyQ) expansion in Huntingtin protein (HttWe demonstrated that potentiating effects of dopamine are mediated by D 1 -class dopamine receptors (DARs) and not by D 2 -class DARs. Consistent with in vitro findings, in whole-animal experiments we found that persistent elevation of striatal dopamine levels exacerbated the behavioral motor deficits and MSN neurodegeneration in YAC128 mice. We further discovered that the clinically relevant dopamine pathway inhibitor tetrabenazine alleviated the motor deficits and reduced striatal cell loss in YAC128 mice. Our results suggest that dopamine signaling pathway plays an important role in HD pathogenesis and that antagonists of dopamine pathway such as tetrabenazine or dopamine receptor blockers may have a therapeutic potential for treatment of HD beyond well established "symptomatic" benefit.

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Section: Pharmacology Of Dopamine/glutamate-induced Apoptosis Of Hd Msnsmentioning

confidence: 65%

Section: Dopaminergic Signaling and Neurodegeneration Of Hd Msnsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Dopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease

Tang¹,

Chen²,

Liu³

et al. 2007

J. Neurosci.

188

190

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“…It was confirmed that NR2B subtype NMDA receptors activation triggers the selective degeneration of the medium spinal striatal neurons in HD [204]. Mutant huntingtin may increase the number of functional NR1/NR2B-type receptors at the cell surface [205]. Moreover, the expression of polyglutamine-expanded huntingtin results in NMDA receptors sensitization and promotes neuronal apoptosis triggered by glutamate [206].…”

Section: Huntington's Diseasementioning

confidence: 87%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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“…[71][72][73][74] Örneğin, aynı glutamat uyarımının uygulanması ve aynı reseptör yoğunluğunda, NR1/NR2A NR1/NR2B'den daha geniş akım amplitüdü gösterir ve daha hızlı de-aktive olur; ancak sonuçta her ikisi de hücre için eşit akım alışı gösterir. 75 Beyinde, gelişim sırasında NR1'ın sekiz farklı kesim çeşidinden (NR1A-H) en az bir tanesi tüm nöronlarda ifade edilirken, NR2 alt üniteleri daha farklı bir dağılım göstermektedir. 76 Prenatal dö-nemde NR2B ve NR2D mRNA'ları baskın durumdayken, NR2A ve NR2C mRNA'ları ancak doğuma yaklaşıldığı dönemde tespit edilebilmiştir.…”

Section: N-meti̇l-d-aspartat Reseptörleri̇unclassified

Mechanisms of Toxicity in Huntington’s Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

Tüfekçi¹,

Tunalı²

2012

Turkiye Klinikleri J Med Sci

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201Huntington Hastalığında Toksisite Mekanizmaları ve NMDAR-Aracılı Eksitotoksisitede Poliaminlerin Rolü Ö ÖZ ZE ET T Huntington hastalığı, istemsiz koreik hareketler, bilişsel kayıplar ve psikolojik bozukluklarla karakterize edilen, otozomal dominant geçişli, geç başlangıçlı ve ölümcül bir hastalıktır. Hastalığa sebep olan mutasyon, IT-15 geninin birinci eksonunda tekrar eden CAG bazlarının sayılarındaki artıştır. Mutant genin ifadesi, striyatal gamma aminobütirik asit ileten (GABA-erjik) orta boy dikensi nöronların seçimli ölümüne neden olur. Mutant huntingtin (htt) proteininin konformasyonu, protein yıkımı ve übikütin-proteozom sistemi (UPS), gen yazılımı düzenlemelerin-deki değişimler ve eksitotoksisite, nörodejenerasyonun moleküler mekanizmaları arasındadır. Uyarıcı kimyasalların aşırı miktarı hücreleri sürekli uyararak hassas hücrelerin eksitotoksik ölüm-lerine sebep olurlar. Glutamat da bazal gangliyadan salınan uyarıcı nörotransmiterlerden biridir. Huntington hastalığında striyatal nöronların kaybedilmesi glutamat reseptörü aracılı eksitotoksisitenin patogenezde etkili olabileceğine işaret eder. İyonotrofik glutamat reseptörleri (iGluR) arasın-dan biri olan N-metil-D-Aspartat reseptörleri (NMDAR)'nin uyarılması ve bunu takiben nükleer faktör kappa B (NF ± B) yazılım faktörünün aktivasyonu nöronal ölüm ile sonuçlanır. NMDAR, glutamat bağlanma bölgelerine ek olarak poliamin bağlanma bölgeleri de içerir. Poliaminlerin mutant htt proteininin, NMDAR ve NF ± B yazılım faktörü ile ayrı ayrı ilişki içerisinde olması, bu proteinin, Huntington hastalığında meydana gelen nörodejenerasyonda merkezi bir rol oynayabileceğini düşündürmektedir. Bu nedenle, Huntington hastalığında poliamin metabolizmasının detaylı araştı-rılması ve anlaşılması hastalığın tedavisinde yeni yaklaşımlar üretilmesini sağlayacaktır.A An na ah ht ta ar r K Ke el li im me el le er r: : Huntington hastalığı; NR2A NMDA reseptörü; reseptörler, glutamat; poliaminler A AB BS ST TR RA AC CT T Huntington's Disease is an autosomal dominant, late onset and fatal disorder characterized by involuntary choreic movements, cognitive dysfunction and psychological disturbances. The causative mutation is the expansion of the CAG repeats in the first exon of the IT-15 gene. Mutant gene expression causes selective death of striatal gamma aminobutyric acid releasing (GABA-ergic) medium size spiny neurons. Changes in the conformation of the mutant huntingtin (htt) protein, proteolysis and ubiquitin-proteasome system (UPS), transcriptional disregulation and excitotoxicity are among the molecular mechanisms of neurodegeneration. Excess amounts of excitatory chemicals continuously stimulate the cells and cause excitotoxic death of vulnerable cells. Glutamate is one of the excitatory neurotransmitters released from basal ganglia. The striatal neuron loss in Huntington's Disease points out that glutamate receptor mediated excitotoxicity may play a role in the pathogenesis. Excitation of N-methyl-D-Aspartate receptors (NMDARs), which belong to ionotrophic glutamate recept...

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Subtype‐Specific Enhancement of NMDA Receptor Currents by Mutant Huntingtin

Cited by 177 publications

References 70 publications

Dopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease

Dopaminergic Signaling and Striatal Neurodegeneration in Huntington's Disease

Ion Channels as Drug Targets in Central Nervous System Disorders

Mechanisms of Toxicity in Huntington’s Disease and the Role of Polyamines in NMDAR-Mediated Excitotoxicity: Review

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