阿片受体脱敏作用中G蛋白偶联受体激酶和arrestin的研究进展

临床上,许多病人使用阿片类药物来缓解疼痛,但由于反复或长期使用导致的耐受和依赖而限制其应用。长期使用阿片受体激动剂会导致受体本身适应性变化,称为阿片受体的脱敏(desensitization),包括受体与G蛋白脱偶联、受体内吞和下调[1]。阿片受体的脱敏是其信号途径调节的重要机制,与耐受的形成密切相关。越来越多的研究显示,G蛋白偶联受体激酶(G protein coupled receptor kinases,GRKs)所介导的受体磷酸化,以及β-arrestin的结合与阿片受体脱敏之间具有密切关系,提示了GRKs和arrestin在调节阿片受体脱敏中具有关键性作用。本文综述了GRK…     

血管内皮生长因子受体的研究进展

血管内皮生长因子受体主要在内皮细胞上表达，可介导多种生理效应，其体内表达水平受低氧及细胞因子等环境因素调节，随着现代分生物学技术的发展，对其结构、功能及两者的关系有了较深入的研究，而可溶性受体将是今后研究的热点。     

失敏态烟碱样受体

烟碱样受体属于配体门控性离子通道受体 ,参与调节体内许多生理过程。激动剂反复作用可以诱导N受体失敏 ,许多因素参与调节烟碱样受体的失敏 ,如受体亚单位、信号转导系统、细胞微环境的变化等都会影响受体的失敏过程。失敏态N受体并非处于无功能状态 ,它们可能参与调节递质的释放、调节突触可塑性等过程     

胆汁酸代谢相关核受体的研究进展

胆汁酸是胆固醇代谢的主要终产物,也是肝和小肠对食物中的脂类进行分解、吸收与转运的重要成分。体内多种核受体参与胆汁酸的代谢调节,如法呢醇受体、孕烷X受体、组成性雄烷受体、维生素D受体、肝X受体α、过氧化物酶体增殖物激活受体等。核受体调节胆汁酸代谢的研究近年来已成为国内外研究的热点,研究胆汁酸代谢相关的核受体,对于了解胆汁酸代谢的调节机制,指导胆汁酸代谢相关疾病的临床合理用药以及探索新药等方面有重要意义。     

雌激素受体与肿瘤发生的研究进展

雌激素属于类固醇激素家族,与受体结合后调节靶基因的转录,在生物体内对维持正常的生命活动起重要作用。雌激素受体(Estrogen receptor,ER)是雌激素作用的靶位点,在相关信号通路中起主要作用,参与调节和维持生命体的基本活动。但雌激素受体表达异常对其靶器官肿瘤如乳腺癌、卵巢癌、子宫内膜癌等的发生有重大影响,还会影响雌激素非靶器官肿瘤的发生,如结肠癌、肺癌等。文章主要就经典的雌激素核受体ERα和ERβ与几种常见肿瘤的相关研究进展进行综述,为雌激素肿瘤防治及其靶向药物的开发提供理论依据。     

脑缺血后谷氨酸及其受体介导的神经细胞损伤及相关药物研究进展

脑缺血损伤涉及多种病理过程,其中兴奋性毒性是关键机制之一。谷氨酸是脑内主要的兴奋性递质,谷氨酸及其受体的病理变化是引起兴奋性毒性的重要病理基础。该文综述了脑缺血后谷氨酸异常释放、谷氨酸受体表达变化及受体后信号传导等病理机制,及以上述机制为靶点的药物研究进展。     

雌性激素受体甲基化与中枢神经系统疾病的研究进展

DNA甲基化作为一种主要的表观遗传修饰模式，与许多疾病的发生及发展相关。近年来研究发现，雌激素对中枢神经系统具有保护作用。雌激素的作用通过雌激素受体发挥。雌激素受体在中枢及外周均有分布，而雌激素受体甲基化异常会影响表达，并会引起缺血性脑卒中、阿尔茨海默病、帕金森病等多种中枢神经系统疾病。该文总结了近年来关于体内雌激素受体甲基化过程以及对中枢神经系统相关疾病的研究进展。     

孕烷X受体生物特性及其在药物代谢中的作用研究进展

核受体孕烷X受体是一类生物体内广泛分布的激素和环境感受器,不仅可参与能量、胆固醇、胆汁酸等物质的代谢以及调节炎症反应,还可以调控工相、Ⅱ相药物代谢酶和相关药物转运蛋白的表达而调节药物代谢,其作用对维持机体诸如细胞增殖分化、生长发育、新陈代谢、稳态维持等多种生理功能有重要意义。本文就孕烷x受体结构功能、生物学效应以及其对药物代谢酶和药物转运调节的作用等作一综述。     

蛋白激酶在阿片受体脱敏中的作用

阿片类镇痛药耐受性在受体水平的变化包括：受体下调、内吞和G蛋白脱偶联。在阿片受体的信号转导过程中，蛋白激酶(PKA，PKC，CaMKⅡ，GRK和MAPK)对阿片类镇痛药的耐受性、依赖性及阿片受体与谷氨酸受体之间的相互作用等方面起作用。本文综述了蛋白激酶在阿片受体脱敏中的作用。     

半胱氨酰白三烯受体拮抗剂对脑缺血的保护作用

炎症是影响脑缺血急性损伤严重程度以及慢性期恢复的主要因素之一,而半胱氨酰白三烯是体内最重要的炎症介质之一,通过半胱氨酰白三烯受体(CysLT1R和CysLT2R)调节脑缺血后炎症等病变。目前,已证实CysLT1R拮抗剂对脑缺血动物模型急性和亚急性/慢性损伤的保护作用,其神经元保护作用可能是间接通过调节胶质细胞,对星形胶质细胞增殖及胶质疤痕形成则有明确的抑制作用。CysLT2R拮抗剂还有待深入研究,但可能与神经元和星形胶质细胞损伤、小胶质细胞激活等有密切关系。CysLT1R和Cys-LT2R拮抗剂是抗脑缺血损伤潜在的新型治疗药物。     

Opioid Receptors and Signaling on Cells from the Immune System

This review discusses the criteria for determining whether a binding site or functional response is directly mediated by either the mu, delta, or kappa opioid receptors. In 1988, Sibinga and Goldstein published the first review that addressed whether cells from the immune system express opioid receptors. The criteria that they used, namely, structure–activity relationships, stereoselectivity, dose- and concentration-dependence, and saturability are still relevant criteria today for determining if an immunological response is mediated by either the mu, delta or kappa opioid receptors. Radioligand receptor binding studies and functional studies that clearly show the presence of an opioid receptor on immunocytes are presented. Selective agonists and antagonists for the mu, delta, and kappa opioid receptors are discussed, and the need for their use in experiments is emphasized. Conditions used in functional assays are very important. Receptor desensitization and downregulation occur within minutes after the application of an agonist. However, many immunological assays are applying an agonist for days before measuring an immunological effect. The results obtained may reflect changes that are results of receptor desensitization and/or downregulation instead of changes that are observed with acute activation of the receptor. The future of receptor pharmacology lies in the crosstalk and dimerization of G protein-coupled receptors. In transfected systems, opioid receptors have been shown to dimerize with chemokine and cannabinoid receptors, resulting in crosstalk between different types of receptors.     

Targeting metabotropic glutamate receptors for treatment of the cognitive symptoms of schizophrenia

Several lines of evidence implicate NMDA receptor dysfunction in the cognitive deficits of schizophrenia, suggesting that pharmacological manipulation of the NMDA receptor may be a feasible therapeutic strategy for treatment of these symptoms. Although direct manipulation of regulatory sites on the NMDA receptor is the most obvious approach for pharmacological intervention, targeting the G-protein coupled metabotropic glutamate (mGlu) receptors may be a more practical strategy for long-term regulation of abnormal glutamate neurotransmission. Heterogeneous distribution, both at structural and synaptic levels, of at least eight subtypes of mGlu receptors suggests that selective pharmacological manipulation of these receptors may modulate glutamatergic neurotransmission in a regionally and functionally distinct manner. Two promising targets for improving cognitive functions are mGlu5 or mGluR2/3 receptors, which can modulate the NMDA receptor-mediated signal transduction by pre- or postsynaptic mechanisms. Preclinical studies indicate that activation of these subtypes of mGlu receptors may be an effective strategy for reversing cognitive deficits resulting form reduced NMDA receptor mediated neurotransmission.     

Calcineurin acts via the C-terminus of NR2A to modulate desensitization of NMDA receptors

Phosphatase IIb (calcineurin, CaN) can reduce N-methyl-D-aspartate (NMDA) synaptic responses by enhancing glycine-independent desensitization. We examined the action of CaN on desensitization in recombinant NMDA receptors comprised of NMDA receptor 1 (NR1) and NR2A subunits. The C-terminus of NR2A, but not NR1, was critical for modulation of desensitization by CaN. Alanine-scanning mutagenesis indicated that serines 900 and 929 in NR2A altered desensitization, as did inhibition of tyrosine phosphatases. Our data suggest that dephosphorylation-dependent regulation of the C-terminus of NR2A increases desensitization of NMDA receptors, providing an additional mechanism for modulation of synaptic signals.     

Acute Opioid Receptor Desensitization And Tolerance: Is There A Link?

1. Morphine, used long-term for the treatment of pain, results in drug tolerance. The therapeutic benefits, as well as side effects, of morphine are mediated predominantly via activation of mu-opioid receptors. Although the underlying mechanisms for opioid tolerance remains unclear, early adaptive processes, such as acute receptor desensitization and receptor downregulation, have been suggested to be crucial to the development of opioid tolerance. 2. Other neuroadaptations resulting from chronic opioid use include upregulation of the cAMP pathway, an increase in the cAMP response element-binding protein and Fos-related antigens. However, the connection between upregulation of these cellular elements and the mechanism behind the behavioural phenomenon remains unclear. 3. Acute receptor desensitization is thought to occur via uncoupling of the receptor and G-protein, which is followed by internalization of the receptor from the cell membrane. This process occurs after a few minutes of agonist exposure. Receptor-G-protein uncoupling is mediated via phosphorylation of putative sites on the intracellular loops of activated receptors. 4. Acute desensitization and downregulation of receptors both result in a reduction of agonist efficacy. These events occur early in the cascade of cellular adaptation; however, it is uncertain whether these processes contribute to the long-term changes in receptor sensitivity that occur after repeated exposure to opioids. 5. Acute desensitization may, in fact, be a protective mechanism whereby cells adapt to avoid the development of physiological drug tolerance by rapidly attenuating receptor-mediated signalling. Those drugs that do not cause receptor internalization, such as morphine, may have higher propensities to develop tolerance.     

N和M胆碱能受体之间的相互调节

N和M胆碱能受体拥有同一种内源性配基ACh ,并且在多种组织中两种受体共存 ,两者之间存在着多种相互作用。如副交感神经节后N受体可通过刺激胆碱能神经纤维末梢释放ACh来调节组织中M受体的功能 ;而胆碱能神经元突触后N受体的活性也可被突触前膜上M和N的自受体通过反馈调控节前纤维ACh的释放来调节 ;另外 ,N受体被阻断或失敏后不同组织中M受体的功能会发生不同的变化 ,以将机体胆碱能神经系统维持在一个稳定状态     

Role of spinal 5-HT receptors in cutaneous hypersensitivity induced by REM sleep deprivation

Previous studies indicate that rapid eye movement (REM) sleep deprivation facilitates pain sensitivity. Since serotoninergic raphe neurons are involved both in regulation of sleep and descending pain modulation, we studied whether spinal 5-HT receptors have a role in sleep deprivation-induced facilitation of pain-related behavior. REM sleep deprivation of 48h was induced by the flower pot method in the rat. The pain modulatory influence of various serotoninergic compounds administered intrathecally was assessed by determining limb withdrawal response to monofilaments. REM sleep deprivation produced a marked hypersensitivity. Sleep deprivation-induced hypersensitivity and normal sensitivity in controls were reduced both by a 5-HT(1A) receptor antagonist (WAY-100635) and a 5-HT(2C) receptor antagonist (RS-102221). An antagonist of the 5-HT(3) receptor (LY-278584) failed to modulate hypersensitivity in sleep-deprived or control animals. Paradoxically, sensitivity in sleep-deprived and control animals was reduced not only by a 5-HT(1A) receptor antagonist but also by a 5-HT(1A) receptor agonist (8-OHDPAT). The results indicate that serotoninergic receptors in the spinal cord have a complex role in the control of sleep-deprivation induced cutaneous hypersensitivity as well as baseline sensitivity in control conditions. While endogenous serotonin acting on 5-HT(1A) and 5-HT(2C) receptors may facilitate mechanical sensitivity in animals with a sleep deprivation-induced hypersensitivity as well as in controls, increased activation of spinal 5-HT(1A) receptors by an exogenous agonist leads to suppression of mechanical sensitivity in both conditions. Spinal 5-HT(3) receptors do not contribute to cutaneous hypersensitivity induced by sleep deprivation.     

Recent advances in molecular pharmacology of the histamine systems: regulation of histamine H1 receptor signaling by changing its expression level

Histamine H1 receptor (H1R) signaling is regulated by changing its expression level. Two mechanisms are involved in this regulation. One is down-regulation through receptor desensitization. Receptor phosphorylation seemed crucial because stimulation of the mutant H1R lacking five putative phosphorylation sites did not show down-regulation. The phosphorylation level of the mutant receptor was much smaller than that of the wild type ones by several protein kinases. The other is up-regulation through activation of receptor gene expression. Protein kinase C (PKC) signaling was suggested to be involved in this up-regulation. Regulation of H1R expression level was mediated not only through H1R but also autonomic nerve receptors. Stimulation of M3 muscarinic receptors (M3R) induced both down-regulation and up-regulation of H1R. Down-regulation of M3R-mediated H1R seemed not to be mediated by PKC activation, although PKC activation induced H1R phosphorylation. Elevation of H1R expression was induced by the stimulation of M3Rs. PKC was suggested to be involved in this up-regulation. Stimulation of beta2-adrenergic receptors induced H1R down-regulation through several mechanisms. One of them is enhanced receptor degradation after desensitization and another is suppression of receptor synthesis that includes the suppression of receptor gene expression and enhanced degradation of the receptor mRNA. Protein kinase A was suggested to be involved in enhanced degradation and the activation of the receptor gene expression. Elevation of both H1R expression and its mRNA was observed in nasal mucosa of nasal hypersensitivity allergy model rat after toluene diisocyanate provocation. These results suggest that activation of H1R gene expression plays an important patho-physiological role in allergy. Elevation of the mRNA was partially but significantly suppressed by antihistamines.     

Pharmacological endothelin receptor interaction does not occur in veins from ET(B) receptor deficient rats

Heterodimerization of G-protein coupled receptors can alter receptor pharmacology. ET A and ET B receptors heterodimerize when co-expressed in heterologous expression lines. We hypothesized that ET A and ET B receptors heterodimerize and pharmacologically interact in vena cava from wild-type (WT) but not ET B receptor deficient (sl/sl) rats. Pharmacological endothelin receptor interaction was assessed by comparing ET-1-induced contraction in rings of rat thoracic aorta and thoracic vena cava from male Sprague Dawley rats under control conditions, ET A receptor blockade (atrasentan, 10 nM), ET B receptor blockade (BQ-788, 100 nM) or ET B receptor desensitization (Sarafotoxin 6c, 100 nM) and ET A plus ET B receptor blockade or ET A receptor blockade plus ET B receptor desensitization. In addition, similar pharmacological ET receptor antagonism experiments were performed in rat thoracic aorta and vena cava from WT and sl/sl rats. ET A but not ET B receptor blockade or ET B receptor desensitization inhibited aortic and venous ET-1-induced contraction. In vena cava but not aorta, when ET B receptors were blocked (BQ-788, 100 nM) or desensitized (S6c, 100 nM), atrasentan caused a greater inhibition of ET-1-induced contraction. Vena cava from WT but not sl/sl rats exhibited similar pharmacological ET receptor interaction. Immunocytochemistry was performed on freshly dissociated aortic and venous vascular smooth muscle cells to determine localization of ET A and ET B receptors. ET A and ET B receptors qualitatively co-localized more strongly to the plasma membrane of aortic compared to venous vascular smooth muscle cells. Our data suggest that pharmacological ET A and ET B receptor interaction may be dependent on the presence of functional ET B receptors and independent of receptor location.     

Agonist-selective mechanisms of GPCR desensitization

The widely accepted model of G protein-coupled receptor (GPCR) regulation describes a system where the agonist-activated receptors couple to G proteins to induce a cellular response, and are subsequently phosphorylated by a family of kinases called the G protein-coupled receptor kinases (GRKs). The GRK-phosphorylated receptor then acts as a substrate for the binding of a family of proteins called arrestins, which uncouple the receptor and G protein so desensitizing the agonist-induced response. Other kinases, principally the second messenger-dependent protein kinases, are also known to play a role in the desensitization of many GPCR responses. It is now clear that there are subtle and complex interactions between GRKs and second messenger-dependent protein kinases in the regulation of GPCR function. Functional selectivity describes the ability of agonists to stabilize different active conformations of the same GPCR. With regard to desensitization, distinct agonist-activated conformations of a GPCR could undergo different molecular mechanisms of desensitization. An example of this is the mu opioid receptor (MOPr), where the agonists morphine and [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) induce desensitization of the MOPr by different mechanisms, largely protein kinase C (PKC)- or GRK-dependent, respectively. This can be best explained by supposing that these two agonists stabilize distinct conformations of the MOPr, which are nevertheless able to couple to the relevant G-proteins and produce similar responses, yet are sufficiently different to trigger different regulatory processes. There is evidence that other GPCRs also undergo agonist-selective desensitization, but the full therapeutic consequences of this phenomenon await further detailed study.     

Biochemical and cell biological mechanisms of cholecystokinin receptor regulation

Regulation of the cholecystokinin receptor is accomplished by biochemical and cell biological mechanisms. The major mechanism for biochemical regulation involves phosphorylation of serine and threonine residues within the receptor's intracellular third loop and carboxyl-terminal tail. This form of rapid desensitization is achieved by protein kinase C, a kinase activated in the normal signaling cascade of this Gq-coupled receptor, and/or a member of the G protein-coupled receptor kinase family that recognizes the active conformation of the receptor. Conversely, a type 2A serine protein phosphatase has been shown to selectively act on this receptor in an agonist-regulated manner, resulting in receptor dephosphorylation and resensitization. Cell biological mechanisms for desensitization involve the net removal of receptors from exposure to circulating hormone via insulation within a specialized plasma membrane domain or internalization into the cell within endocytic compartments. Internalization has been shown to occur by both clathrin-dependent and clathrin-independent mechanisms, the latter believed to represent potocytosis in caveolae, that lead to recycling of receptors to the plasma membrane for resensitization or shuttling of receptors to lysosomes for degratory down-regulation. Interestingly, receptor phosphorylation has been shown to affect intracellular domain accessibility and receptor trafficking, although the specific proteins regulating this have not yet been identified. The cholecystokinin receptor can exist in the plasma membrane as oligomeric superstructures, namely as homomers with themselves or as heteromers with closely related class I G protein-coupled receptors. Agonist occupation results in oligomer dissociation, but the functional significance of this observation has yet to be defined.