多巴胺受體D2
多巴胺受體D2(Dopamine receptor D2,簡稱D2R),為轉譯自 DRD2 基因的一種多巴胺受體蛋白。D2R最早於1975年為Philip Seeman所發現,並將其命名為「抗精神疾患性多巴胺受體」(antipsychotic dopamine receptor)[8]。D2R為所有抗精神病藥物的作用標的。
功能
D2R屬於一種多巴胺受體,並會與Gi結合。Gi為G蛋白偶聯受體的一種亞型,會抑制腺苷酸環化酶的活性[9]。
在小鼠模式中,齒狀回的neuronal calcium sensor-1(NCS-1)會影響D2R在細胞膜的表現量。這項機制會影響突觸可塑性及記憶形成[10]。
同型體
長形式(D2Lh)具有"規範"的序列,並作為經典突觸後蛋白發揮作用。[13]短形式(D2Sh)在突觸前作為調節突觸間隙中多巴胺水平的自身受體發揮作用。[13]D2Sh受體激動時抑制多巴胺釋放,拮抗時增加多巴胺釋放。[13]第三種D2(更長)的形式不同於270V被VVQ取代的規範序列。[14]
基因組
等位基因變異:
- A-241G
- C132T、G423A、T765C、C939T、C957T,以及G1101A[15]
- Cys311Ser
- -141C insertion/deletion[16]The polymorphisms have been investigated with respect to association with schizophrenia.[17]
Some researchers have previously associated the polymorphism Taq 1A (rs1800497) to the DRD2 gene. However, the polymorphism resides in exon 8 of the ANKK1 gene.[18]DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease.[19][20]
配體
大多數較老的抗精神病藥如氯丙嗪或氟哌啶醇是多巴胺D2受體的非選擇性拮抗劑,最多僅對"D2樣家族"受體具有選擇性,因此與D2、D3、D4以及許多其他受體都可以結合,例如血清素和組織胺受體,導致一系列副作用使得它們不適合科學研究。類似,用於治療巴金森氏症的較舊的多巴胺促效劑例如溴隱亭和卡麥角林,對一種多巴胺受體的選擇性較差,儘管這些藥物中大多數確實能起到D2促效劑的作用,但它們也會影響其他多巴胺受體,亞型也是。現今有幾種選擇性D2配體 (生物化學)可以使用,並且隨著進一步的研究,這個數字可能會增加。
受體致活劑
- 溴隱亭(Bromocriptine):完全受體致活劑
- Cabergoline(Caberl)
- N,N-Propyldihydrexidine:D1/D5受體制活劑dihydrexidine的類似物,對節後神經元的D2R親和性比節前神經元的D2自體受器高。
- Piribedil:同時也是 D3 受體致活劑及腎上腺素α2受體拮抗劑
- Pramipexole:同時也是D3、D4受體致活劑
- Quinelorane:affinity for D2 > D3
- Quinpirole:同時也是D3受體致活劑
- Ropinirole:完全受體致活劑
- Sumanirole:高選擇性完全受體致活劑
- Talipexole:對D2的親和性高於其他的多巴胺受體,但同時也是腎上腺素α2受體制活劑及5-HT3受體拮抗劑。
部分受體致活劑
- Aplindore
- 阿立哌唑(Aripiprazole,在美國合法)[21]
- Brexpiprazole/OPC-34712
- Cariprazine
- RP5063
- GSK-789,472 – Also D3 antagonist, with good selectivity over other receptors [22]
- 氯胺酮(Ketamine,同時也為NMDA受體拮抗劑)
- LSD – in vitro, LSD was found to be a partial agonist and potentiates dopamine-mediated prolactin secretion in lactotrophs.[23]LSD is also a 5-HT2A agonist.
- 莫達非尼(Modafinil)
- Roxindole (only at the D2 autoreceptors)
- OSU-6162:亦為5-HT2A部分受體致活劑,acts as "dopamine stabilizer"
- Salvinorin A:亦為κ-鴉片類受體致活劑。
受體拮抗劑
- Atypical antipsychotics
- Desmethoxyfallypride
- Domperidone – D2 and D3 antagonist; does not cross the blood-brain barrier
- Eticlopride
- Fallypride
- Hydroxyzine (Vistaril, Atarax)
- Itopride
- L-741,626 – highly selective D2 antagonist
- C11 Raclopride radiolabled – commonly employed in positron emission tomography studies[24]
- Typical antipsychotics
- SV 293[25]
- Yohimbine
- D2sh selective (presynaptic autoreceptors)
異位調控因子
Functionally selective ligands
- 參見參考文獻[31]。
Protein–protein interactions
多巴胺受體 D2 已被證明與EPB41L1、[32]PPP1R9B[33] 和 NCS-1 相互作用。[34]
Receptor oligomers
The D2 receptor forms receptor heterodimers in vivo (in living animals) with other G protein-coupled receptors; these include:[35]
The D2 receptor has been shown to form hetorodimers in vitro (and possibly in vivo) with DRD3,[38]DRD5,[39]and 5-HT2A.[40]
註釋
- ^ D2sh–TAAR1 is a presynaptic heterodimer which involves the relocation of TAAR1 from the intracellular space to D2sh at the plasma membrane, increased D2sh agonist binding affinity, and signal transduction through the calcium–PKC–NFAT pathway and G-protein independent PKB–GSK3 pathway.[36][37]
參考文獻
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- ^ 對Dopamine receptor D2, isoform CRA_c起作用的藥物;在維基數據上查看/編輯參考.
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This original observation of TAAR1 and DA D2R interaction has subsequently been confirmed and expanded upon with observations that both receptors can heterodimerize with each other under certain conditions ... Additional DA D2R/TAAR1 interactions with functional consequences are revealed by the results of experiments demonstrating that in addition to the cAMP/PKA pathway (Panas et al., 2012) stimulation of TAAR1-mediated signaling is linked to activation of the Ca++/PKC/NFAT pathway (Panas et al.,2012) and the DA D2R-coupled, G protein-independent AKT/GSK3 signaling pathway (Espinoza et al., 2015; Harmeier et al., 2015), such that concurrent TAAR1 and DA DR2R activation could result in diminished signaling in one pathway (e.g. cAMP/PKA) but retention of signaling through another (e.g., Ca++/PKC/NFA)
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Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity.
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外部連結
- 醫學主題詞表(MeSH):Receptors,+Dopamine+D2
- Pappas, Stephanie. Study: Genes Influence Who Your Friends Are. Imaginova Corp. LiveScience. [20 January 2011].