维生素D及其受体在帕金森病中的作用

帕金森病(Parkinson's disease,PD)是一种常见的中枢神经系统退行性疾病,引起帕金森病的发病机制至今尚未明确。帕金森病患者及老年人普遍存在维生素D缺乏,这可能是帕金森病的重要发病机制之一。由于维生素D具有免疫调节,抗氧化,调节神经营养因子,降低神经毒性的功能,能同时针对几种导致神经退行性病变因素发挥作用,特别是老年人纠正维生素D缺乏可能会阻止神经元的损失和PD相关的认知功能下降。因此补充维生素D可能成为治疗PD的方法。近年来研究发现,维生素D受体基因多态性与帕金森病的发病有相关性。该文就维生素D及其受体在帕金森病中可能发生的保护作用及其机制作一综述。     

Dopamine D(1) and D(3) receptors oppositely regulate NMDA- and cocaine-induced MAPK signaling via NMDA receptor phosphorylation

Development of drug addiction involves complex molecular changes in the CNS. The mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in mediating neuronal activation induced by dopamine, glutamate, and drugs of abuse. We previously showed that dopamine D(1) and D(3) receptors play different roles in regulating cocaine-induced MAPK activation. Although there are functional and physical interactions between dopamine and glutamate receptors, little is known regarding the involvement of D(1) and D(3) receptors in modulating glutamate-induced MAPK activation and underlying mechanisms. In this study, we show that D(1) and D(3) receptors play opposite roles in regulating N-methyl-d-aspartate (NMDA) -induced activation of extracellular signal-regulated kinase (ERK) in the caudate putamen (CPu). D(3) receptors also inhibit NMDA-induced activation of the c-Jun N-terminal kinase and p38 kinase in the CPu. NMDA-induced activation of the NMDA-receptor R1 subunit (NR1), Ca(2+)/calmodulin-dependent protein kinase II and the cAMP-response element binding protein (CREB), and cocaine-induced CREB activation in the CPu are also oppositely regulated by dopamine D(1) and D(3) receptors. Finally, the blockade of NMDA-receptor reduces cocaine-induced ERK activation, and inhibits phosphorylation of NR1, Ca(2+)/calmodulin-dependent protein kinase II, and CREB, while inhibiting ERK activation attenuates cocaine-induced CREB phosphorylation in the CPu. These results suggest that dopamine D(1) and D(3) receptors oppositely regulate NMDA- and cocaine-induced MAPK signaling via phosphorylation of NR1.     

Structure-activity relationship studies on vitamin D lactam derivatives as vitamin D receptor antagonist

Structure–activity relationship studies on 1α,25-dihydroxyvitamin D₃-26,23-lactams (DLAMs), antagonists of vitamin D, were conducted, focusing on the substituents of the phenyl group. One of the derivatives (23S,25S)-DLAM-1P-3,5(OEt)₂, showed potent antagonistic activity with an IC₅₀ of 90 nM.     

Exons and functional regions of the human vitamin D receptor gene around and within the main 1a promoter are well conserved among mammals

The human vitamin D receptor (hVDR) gene encompasses eight exons (2–9) in the so-called coding region and six more exons (1a–1f) in the so-called regulatory region, which contains several reported promoters. Evolutionary comparison performed on the VDR promoter sequences of a dozen of mammalian species shows a very high conservation of numerous regions around and in the 1a promoter, including exons 1e, 1a and 1d, and the Sp1 site region. This suggests that the so-called 1a promoter is well conserved among mammals. Homology among mammals also concerns three functional SNP site regions of the hVDR 1a promoter, the 1e-G-1739A SNP region (a Cdx-2 binding site), and both 1a-G-1521C and 1a-A-1012G sites, the 1a-1012A being located within a GATA site. Interestingly, the 1521G and 1012A nucleotides are being evolutionary conserved, suggesting that the 1521C/1012G haplotype, which is found in human chromosomes (43% of Caucasians), is a human specificity.     

前列腺素D2与睡眠调节

前列腺素D2（PGD2）是目前已知最有潜力的内源性促睡眠物质之一。鼠脑脊液（CSF）中PGD2浓度与睡眠－觉醒周期一致,呈现节律性改变,并且随睡眠剥夺期间嗜睡倾向增加而增加,催化PGH2转变为PGD2的特生酶有两种：Lipocalin型前列腺素D合成酶（L－PGDS）和脾型PGDS。L－PGDS主要在大脑蛛网膜和脉络丛产生,并分泌入CSF。L－PGDS和PGD2在脑室系统、蛛网膜下腔及细胞外间隙中循环,循环中的PGD2可与前脑头端基底腹内侧面的化学感受器中的前列腺素D2受体（DPR）相互作用,通过活化具有腺苷A2a受体的元以产生促进睡眠的信号。PGD2敏感区内DPR的活化可导致腹侧视前区（VLPO）内神经元的活化,其可通过抑制结节乳头核（TMN）而促进睡眠。相反,PGE2在维持大脑清醒状态下起主要作用。PGD2和PGE2的平衡对正常睡眠－觉醒周期的维持十分关键。     

Integrin triplets of marine sponges in human D2 receptor heteromers

The evidence for the existence of receptor heteromers opens up a new field for a better understanding of neural transmission. Based on our theory, we have discovered main triplets of amino acid residues in cell-adhesion receptors of marine sponges, which appear also as homologies in several dopamine D2 receptor heteromers of human brain. The obtained results probably mean a general molecular mechanism for receptor–receptor interactions in heteromers originated from the lowest animals (marine sponges).     

Potent activation of dopamine D3/D2 heterodimers by the antiparkinsonian agents, S32504, pramipexole and ropinirole

Recombinant, human dopamine D3 and D2 receptors form functional heterodimers upon co-expression in COS-7 cells. Herein, actions of the antiparkinsonian agents, S32504, ropinirole and pramipexole, at D3/D2L heterodimers were compared to their effects at the respective monomers and at split, chimeric D3trunk/D2tail and D2trunk/D3tail receptors: the trunk incorporated transmembrane domains (TDs) I-V and the tail TDs VI and VII. In binding assays with the antagonist [3H]nemonapride, all agonists were potent ligands of D3 receptors showing, respectively, 100-, 18- and 56-fold lower affinity at D2L receptors, mimicking the selective D3 receptor antagonist, S33084 (100-fold). At D3trunk/D2tail receptors, except for ropinirole, all drugs showed lower affinities than at D3 sites, whereas for D2trunk/D3tail receptors, affinities of all drugs were higher than at D2L sites. The proportion of high affinity binding sites recognized by S32504, pramipexole and ropinirole in membranes derived from cells co-expressing D3 and D2L sites was higher than in an equivalent mixture of membranes from cells expressing D3 or D2L sites, consistent with the promotion of heterodimer formation. In contrast, the percentage of high and low affinity sites (biphasic isotherms) recognized by S33084 was identical. Functional actions were determined by co-transfection of a chimeric adenylyl cyclase (AC)-V/VI insensitive to D3 receptors. Accordingly, D3 receptor-transfected cells were irresponsive whereas, in D2L receptor-transfected cells, agonists suppressed forskolin-stimulated cAMP production with modest potencies. In cells co-transfected with D3 and D2L receptors, S32504, ropinirole and pramipexole potently suppressed AC-V/VI with EC50s 33-, 19- and 11-fold lower than at D2L receptors, respectively. S32504 also suppressed AC-V/VI activity at split D3trunk/D2tail and D2trunk/D3tail chimeras transfected into COS-7 cells. In conclusion, antiparkinson agents behave as potent agonists at D3/D2'heterodimers', though any role in their actions in vivo remains to be demonstrated.     

Vitamin D receptor gene polymorphisms (TaqI and ApaI) in relation to 25-hydroxyvitamin D levels and coronary artery disease incidence

Abstract

Context/objective: Previous studies have illustrated the association of the ApaI and TaqI polymorphisms of the vitamin D receptor gene, located in non-coding and coding regions, respectively, with diseases such as cancer and cardiovascular disease; however, investigating such association in Egyptian patients with coronary artery disease (CAD) has never been formerly attempted. Materials and methods: Male patients (n?=?137), 35–50 years of age, with verified CAD, were recruited alongside age- and sex-matched controls (n?=?58). Genotyping and 25-hydroxyvitamin D [25(OH)D] measurement were performed by polymerase chain reaction RFLP and HPLC, respectively. Results: Comparison of the genotypic distribution of both the TaqI and ApaI polymorphisms between patients and controls yielded insignificant results (p?=?0.55 and 0.7, respectively). Comparison of the allelic distribution of both polymorphisms also yielded insignificant results. The TaqI polymorphism was not found to predict 25(OH)D levels, whereas the wild-type genotype of the ApaI polymorphism was associated with greater levels of 25(OH)D (p?=?0.02), taking all subjects into consideration. Discussion/conclusion: This study presents the ApaI and TaqI polymorphisms as non-influencing players in the pathogenesis of CAD in Egyptian males and the ability of only the ApaI polymorphism to predict 25(OH)D levels, thus warranting further investigations of the triangular relationship between the polymorphisms, 25(OH)D and CAD incidence.     

Dopamine D1 receptor interaction with arrestin3 in neostriatal neurons

Dopamine D1 receptor interactions with arrestins have been characterized using heterologously expressed D1 receptor and arrestins. The purpose of this study was to investigate the interaction of the endogenous D1 receptor with endogenous arrestin2 and 3 in neostriatal neurons. Endogenous arrestin2 and 3 in striatal homogenates bound to the C-terminus of the D1 receptor in a glutathione-S-transferase (GST) pulldown assay, with arrestin3 binding more strongly. The D1 C-terminus and, to a lesser extent, the third cytoplasmic loop also bound purified arrestin2 and 3. In neostriatal neurons, 2, 5, and 20 min agonist treatment increased the colocalization of the D1 receptor and arrestin3 immunoreactivity without altering the colocalization of the D1 receptor and arrestin2. Further, agonist treatment for 5 and 20 min caused translocation of arrestin3, but not arrestin2, to the membrane. The binding of arrestin3, but not arrestin2, to the D1 receptor was increased as assessed by coimmunoprecipitation after agonist treatment for 5 and 20 min. Agonist treatment of neurons induced D1 receptor internalization (35-45%) that was maximal within 2-5 min, a time-course similar to that of the increase in colocalization of the D1 receptor with arrestin3. These data indicate that the D1 receptor preferentially interacts with arrestin3 in neostriatal neurons.     

Immunolocalization of androgen and vitamin D receptors in the epididymis of mature ram (Ovis aries)

This study illustrated the immunohistochemical distribution of androgen and vitamin D receptors of epididymis in 20 sexually mature ram (Rahmani breed) with average age ranged from (2^_4) years and average weight ranged from (50^_65kg). Androgen receptor was localized in the cytoplasm of both ciliated and non ciliated cells of efferent ductules, besides the principal cells via the entire epididymal duct. The principal cells of both corpus and proximal cauda epididymis showed the highest immunoreactivity to androgen receptors. Furthermore, vitamin D receptor was localized in the cytoplasm of all epithelium of the efferent ductules besides principal cells of all epididymal regions, however the immunoreaction was significantly higher in the efferent ductules, distal caput and distal cauda epididymis. In conclusion, these results suggest that the function of ram epididymis is regulated by both androgen and Vitamin D.     

维生素D受体最新研究进展

维生素D受体(vitamin D receptor,VDR)是一种核转录因子,通过与配体特异结合,调控多种基因的表达,从而调节多种生命活动的进行.本文总结了近年来VDR的研究进展,主要包括VDR的作用机制、VDR行使功能所需共激活子及共抑制子、VDR在生长分化、免疫调节和抑制肿瘤等方面的作用及VDR配体类似物在药物开发研究领域的最新进展.     

维生素D与阿尔茨海默病的关系

阿尔茨海默病(Alzheimer disease,AD)是神经科学领域研究最热点的问题之一,同时也是老年痴呆的最常见类型之一。流行病学研究发现老年人血清中维生素D普遍缺乏,而阿尔茨海默病患者血清中维生素D也普遍缺乏,这可能是老年人患阿尔茨海默病的重要原因之一。老年人皮肤合成维生素D前体的能力下降,活动能力下降导致接受日光照射减少,进而影响血清中维生素D含量。近年的研究表明,维生素D具有保护神经元的潜在功能和调节多种大脑靶组织,如提高神经生长因子水平、神经保护作用、提高其抗氧化酶活性、增加抗氧化及水平、降低自由基含量、减少炎症因子的产生及影响APOE基因多态性等,这些功能与AD的病理生理改变相关。这些研究为AD的发病机制及其早期预防和治疗奠定了基础。