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1、,返回目录,返回主页,上一页,细胞的信息处理途径类比计算机的处理网络,细胞间信号传递:从“固电”到“手机”? 2010年07月13日,从细胞分泌到血液循环中的微小核糖核酸(microRNA, miRNA)是一类新的信号分子,介导细胞间和组织器官间的信息传递。南京大学生命科学学院的一篇发表在7月9日的杂志(Molecular Cell)上的研究论文报告了这个新发现:即miRNA能够被一种细胞分泌出来后,经血液循环被运输到另外一种受体细胞内,通过降低其相应的靶基因的翻译,从而调节受体细胞的功能 miRNA是一类动植物细胞内自然产生的非编码小RNA。最近的研究已发现miRNAs参与了几乎所有已知的生
2、物学过程和一些疾病的发生发展。“自从15年前在线虫中发现了首个miRNA以来,miRNA被发现参与调节了众多的细胞功能与发育过程。时至今日,已有约1000个动物的miRNA被报道,且约30%的基因被预测为miRNA的靶基因,能够被miRNA所直接调控。 更有意思的是,“以激素/细胞因子受体及抗原抗体等为代表的已知传统的细胞间信号传递方式,通常发生在特定种类的细胞,并且一般只有一个或数个分子直接作用。因而,这种通信方式是“单通道”的。而因为所有类型的细胞都具有分泌与接受miRNA的能力;并且在特定的生理与病理生理条件下,细胞可一次性分泌多种miRNA,在靶细胞中更能调节多个基因的翻译,所以,mi
3、RNA的分泌作为细胞的信号传递方式是“双通道”或“多通道”的。因此,发现miRNA的分泌即把细胞的信号传递方式从“固定电话”提升为“手机”。总之,该新发现帮助我们更好地理解生物系统内信息传递的本质规律,揭示疾病发生发展的新机制,并发展出新的治疗策略与方法”。,信号传导通路具有级联放大作用,SIGNAL TRANSDUCTION: AMPLIFICATION,第一节 概 述 Introduction,Fundamental Concepts,细胞对外界信号的反应是生命的特征之一。 The ability of cells to receive and act on signals from be
4、yond the plasma membrane is fundamental to life.,细菌与单细胞生物直接对环境刺激作出反应,而多细胞生物尤其是高等生物则需要广泛的细胞间信号交流。 Bacteria and single cell organisms usually respond to environmental changes directly. While multicellular organism cells with different functions need to exchange a wide variety of intercellular signals.
5、 植物主要对生长激素及光线变化等信号起反应。Plant cells respond to growth hormones and to variations in sunlight., 动物细胞则主要对内环境的各种变化作出反应,如离子及各代谢物浓度的感应,各器官组织代谢活性的相互协调,以及胚胎细胞发育的精确调控等。 Animal cells exchange information about the concentrations of ions and glucose in extracellular fluids, the interdependent metabolic activiti
6、es taking place in different tissues, and, in an embryo, the correct placement of cells during development., 以上的各种内外信号均由相应的信息物质(分子)携带,可以被特定的受体识别,通过一定方式传递到细胞内部并引起细胞内的化学改变,从而产生生物效应。这就是细胞的信号转导。 In all these cases, the signal represents information that is detected by specific receptors and converted to
7、 a cellular response, which always involves a chemical process. This conversion of information into a chemical change, signal transduction, is a universal property of living cells.,细胞信号转导的基本过程如下: The common process of signal transduction follows the pathway list below:,特定细胞合成并分泌信号分子 信号分子通过扩散或血液循环到达靶
8、细胞 靶细胞上的受体识别结合信号 通过一系列化学反应将信号转导至细胞内 产生特定生物学效应,some specific cells synthesize and secrete signal molecules signal reach to target cells through diffusion or blood circulation the specific receptor on target cells recognize and bind the signal information are convert to intracellular response via a se
9、ries of chemical reactions corresponding biological effects are generated,细胞通讯(cell communication):指一个细胞发出的信息通过介质传递到另一个细胞产生相应反应的过程。 细胞通讯主要有三种方式: 1 细胞间隙连接 2 膜表面分子接触通讯 3 化学通讯,信号转导(signal transduction): 指外界信号(如光、电、化学分子)与细胞细胞表面受体作用,通过影响细胞内信使的水平变化,进而引起细胞应答反应的一系列过程。 不同信号转导通路之间存在交差对话(cross talk),细胞间隙连接,膜表面
10、分子接触通讯,化学通讯,Cell-cell communication: no signal molecule,Communication between neighboring cells: no signal molecule is needed, direct link (desmosomes, tunneling nanotubules) between the cytoplasms (metabolism of the cells is coordinated),Change in intracytoplasmic Ca+ ion concentration spreads from
11、 one cell to other in case of desmosomally linked cells,Cell-cell communication: signal molecules,Humoral communication between cells: endocrine and paracrine contact,Membrane penetrating (small, hydrophobic) molecules, cytoplasmic receptors, direct effect on gene activity,Hydrophilic molecules, cel
12、l-surface receptors, intracellular signaling second messengers sophisticated signaling and signal-amplification mechanisms,Definitions,The molecules, produced by the signaling cell (hormones, cytokines, growth factors, chemoattractants, neurotransmitters, etc.) are usually called ligands. The molecu
13、les that detect them and interact with them with high specificity and high affinity are called receptors. Receptors are located in the cytoplasm or on the plasmamembrane. The receptors we discuss today are either transcription factors or able to activate transcription factors by intracellular signal
14、ing mechanisms.,Hormones,Endocrine signaling: hormons are produced by endocrine glands, the extracellular signal is secreted into the blood stream, their effect is very specific Paracrine signaling molecules might circulate outside the blood vessels Autocrine factors stimulate the producing cells: i
15、n case of mitogenic factors it could lead to unlimited proliferation,Signaling: 6-7 steps production of the signal, export (secretion), transport, detection (receptor), intracellular signal- transduction, metabolic response, termination of the signal: decomposition of the molecule(s) participating i
16、n the signal,间隙连接(Gap Junction),两个相邻的细胞间存在着一种特殊的由蛋白质构成的结构连接子(Connexon)。连接子两端分别嵌入两个相邻的细胞,形成一个亲水性孔道。这种孔道允许自由交换分子量为1500道尔顿以下的水溶性分子。这种直接交换的意义在于相邻的细胞可以共享小分子物质,因此可以快速和可逆地促进相邻细胞对外界信号的协同反应。连接子为一个多基因家庭,现已发现12个成员。在肿瘤生长和创伤愈合等过程中都观察到某些类型连接子表达的变化。因此,连接子可能对细胞的生长、分化、定位及细胞形态的维持具有重要意义。 分布:除骨骼肌细胞及循环血细胞外的细胞之间。,膜表面分子接触
17、通讯,细胞都有众多的分子分布于膜的外表面。这些分子或为蛋白质,或为糖蛋白。这些表面分子作为细胞的触角,可以与相邻细胞的膜表面分子特异性地相互识别和相互作用,以达到功能上的相互协调。这种细胞通讯方式称为膜表面分子接触通讯。膜表面分子接触通讯也属于细胞间的直接通讯,最为典型的例子是T淋巴细胞与B淋巴细胞的相互作用。,化学通讯,细胞可以分泌一些化学物质蛋白质或小分子有机化合物至细胞外,这些化学物质作为化学信号(chemical signaling)作用于其它的细胞(靶细胞),调节其功能,这种通讯方式称为化学通讯。化学通讯是间接的细胞通讯,即细胞间的相互联系不再需要它们之间的直接接触,而是以化学信号为
18、介质来介导的。根据化学信号分子可以作用的距离范围,将其分为三类,返回目录,返回主页,返回目录,返回主页,返回目录,返回主页,返回目录,返回主页,返回目录,返回主页,返回目录,返回主页,膜表面分子接触通讯,细胞都有众多的分子分布于膜的外表面。这些分子或为蛋白质,或为糖蛋白。这些表面分子作为细胞的触角,可以与相邻细胞的膜表面分子特异性地相互识别和相互作用,以达到功能上的相互协调。这种细胞通讯方式称为膜表面分子接触通讯。膜表面分子接触通讯也属于细胞间的直接通讯,最为典型的例子是T淋巴细胞与B淋巴细胞的相互作用。,返回目录,返回主页,化学通讯,细胞可以分泌一些化学物质蛋白质或小分子有机化合物至细胞外,
19、这些化学物质作为化学信号(chemical signaling)作用于其它的细胞(靶细胞),调节其功能,这种通讯方式称为化学通讯。化学通讯是间接的细胞通讯,即细胞间的相互联系不再需要它们之间的直接接触,而是以化学信号为介质来介导的。根据化学信号分子可以作用的距离范围,将其分为三类,化学信号分子的种类及特性,内分泌(endocrine)系统的化学信号称为激素,作用距离最远。 自分泌(autocrine)神经系统的化学信号神经递质(neural transmitter),作用距离最近。 旁分泌(paracrine)系统的化学信号包括各种细胞因子,作用距离介于以上两类之间。,化学信号分类 根据分子作
20、用的距离,内分泌(endocrine)系统 以激素为主,它们是由内分泌器官分泌的化学信号,并随血流作用于全身靶器官。 旁分泌(paracrine)系统 以细胞因子为主,它们主要作用于局部的细胞,作用距离以毫米计算。 自分泌(autocrine)系统 神经介质为主,其作用局限于突触内,作用距离在100nm以内。,细胞信号,1、生物大分子的结构信号: 蛋白质、多糖、核酸的结构信息 2、物理信号:电、光、磁 3、化学信号: 细胞间通讯的信号分子:激素、神经递质与神经肽、局部化学介导因子、抗体、淋巴因子 细胞内通讯的信号分子 :cAMP, cGMP, Ca2+, IP3, DG、NO, 类固醇衍生物:
21、如肾上腺皮质激素、性激素等; 氨基酸衍生物:如甲状腺激素,儿茶酚胺类激素; 多肽及蛋白质:如生长因子、细胞因子、胰岛素、下丘脑激素、垂体激素、甲状旁腺素、胃肠激素等; 脂类衍生物:如前列腺素。 气体分子:如NO,CO等。,细胞间信息物质可按照其化学本质的不同分为五类:,化学信号 根据其溶解性分类,脂溶性化学信号: 脂溶性化学信号可以通过膜脂双层结构进入胞内,其受体位于胞浆或胞核内。 水溶性化学信号: 水溶性化学信号不能进入细胞,其受体位于细胞外表面。 所有的化学号都必须通过与受体结合方可发挥作用.,返回目录,返回主页,第二节 细胞信号转导分子 Extracellular Signals 一,细
22、胞外信号转导分子,细胞外信号,又称第一信使,是指能作用到特定靶细胞并调节其生命活动的化学分子。其化学组成包括蛋白质,多肽,氨基酸及其衍生物,脂类,气体小分子(如CO, NO)等。 Extracellular signal, also called first messenger, refers to the chemical molecules that secreted by specific cells and act on target cells to regulate their life. These molecules include protein or peptide, am
23、ino acids and derivatives, steroid hormones, fatty acid derivatives, and gas molecules (eg, CO, NO).,根据作用方式不同,细胞外信号主要分为四种类型:According to the acting manner, extracellular signal are divided into the following four groups: 1. 神经递质(Neurotransmitters) Neurotransmitters are also called synaptic signal (突
24、触信号). The arrival of an action potential triggers neurotransmitter release from the presynaptic cell. The neurotransmitter diffuses to the postsynaptic cell, binds to specific receptors in the plasma membrane, and triggers a change in transmembrane electrical potential (Vm).,很多重要的神经递质都是由氨基酸衍生的有机胺类。
25、Many important neurotransmitters are primary or secondary amines, derived from amino acids in simple pathways. 在神经递质信号传递中,信号的作用范围很小(微米级)。 In neuronal signaling, the neurotransmitter may travel only a fraction of a micrometer, across the synaptic cleft to the next neuron in a network.,2. 激素(Hormones)
26、 Hormones, also called endocrine signal (内分泌信号), are synthesized by endocrine cells and released into the blood and carried to target cells throughout the body. Many endocrine hormones are nitrogen-containing molecules (含氮化合物), for example, epinephrine and thyroxin are amino acid derivatives, TSH an
27、d glucagon are peptide, insulin and GH are protein. Another moiety are steroid hormones (甾体激素), such as sex hormones, corticosteroid hormone, et al.,非水溶性激素通常直接与细胞内受体结合,而水溶性激素通过结合膜受体作用。Some lipophilic hormones, eg, steroid hormones and thyroxin can enter the cell and induce cell response through bind
28、ing their intracellular receptors. While other water-soluble hormones act on target cells through binding the membrane receptors. 激素与受体的亲和力很高,只需极低的浓度(nM或更低)就可产生效应。Hormones have very high affinity for their receptors, very low concentrations of hormones (nanomolar or less) are sufficient to produce r
29、esponses in target tissues.,3. 局部化学介质(Local chemical mediators) 由特定细胞分泌,通过扩散作用于邻近的靶细胞,又称为旁分泌信号。These signals usually act locally on the target cells that close to where signals are released via diffusion instead of blood stream. They are also referred as paracrine signal. 许多生长因子和细胞因子属于旁分泌信号。Many gro
30、wth factors and cytokines are paracrine signal. The known paracrine signals include histamine, eicosanoids (PGs, TXs, LTs), interleukin, TNFs, CSFs, and somatostatin.,4. 气体信号(Gas signals) (1). The typical one is nitric oxide (NO), and its origin and acting mechanism have been well-characterized. NO
31、is produced from arginine by Ca2+-dependent NO synthase, present in many mammalian tissues. NO is sufficiently nonpolar to cross plasma membranes without a carrier. In the target cell, it binds to the heme group of guanylyl cyclase and activates cGMP production. In the heart, cGMP reduces the forcef
32、ulness of contractions by stimulating the ion pump(s) that expel Ca2+ from the cytosol.,(2). Carbon monoxide (CO) CO is produced by heme oxygenase and is toxic in high concentrations. But the very low concentrations of CO generated during heme degradation appears to have some regulatory and/or signa
33、ling functions. It acts as a vasodilator, much the same as (but less potent than) nitric oxide. Low levels of CO also have some regulatory effects on neurotransmission.,二、细胞内信息物质,在细胞内传递特定调控信号的化学物质称为细胞内信息物质(intracellular signal molecules) 。 细胞内信息物质主要包括:第二信使、第三信使、信号转导蛋白或酶等。,1. 第二信使(second messengers)
34、The interaction of extracellular signals with receptors on the cell surface often leads to the production of second messengers inside the cell, which in turn leads to adaptive changes in the cell interior. There are many kinds of intracellular transducers, for example, ion (eg,Ca2+), lipid derivativ
35、es (eg, DAG, eicosanoids, and ceramide), carbohydrate derivatives (eg, IP3), nucleotides (eg, cAMP, cGMP), signal proteins (Ras, JAK, and Raf, et al).,二,细胞内信息分子 Intracellular transducer,第二信使:,在细胞内传递信息的小分子化学物质称为第二信使(secondary messenger) 。 第二信使主要包括: 环核苷酸类:如cAMP和cGMP; 脂类衍生物:如甘油二酯(DAG);神经酰胺,花生四烯酸; 无机物:如
36、Ca2+、NO; 糖类衍生物: 1,4,5-三磷酸肌醇(IP3)。,第三信使:,负责细胞核内、外信息传递的物质称为第三信使(third messenger) ,又称为DNA结合蛋白。 第三信使是一类可与靶基因特异序列结合的核蛋白,能调节基因的转录。如立早基因(immediate-early gene)的编码蛋白质 。,细胞核内信号分子 (nuclear transducers) Sometimes, we refer to those proteins responsible for internuclear signaling as third messenger which usually
37、 are transcription factors (转录因子) and/or transcription coordinators (转录调节蛋白) (co-activators, repressors). 蛋白激酶 (protein kinase) The intracellular signaling often involve protein kinase cascade which can amplify millions times of the initial information.,返回目录,返回主页,细胞外信号通讯通常包括六个步骤:,1、合成 2、信号细胞释放信号分子 3
38、、信号分子运输到靶细胞 4、通过特定受体蛋白的信号检测 5、细胞内由受体-信号复合体触发的代谢、功能和发育的改变 6、信号的消除,终止细胞响应,第三节 胞内重要的信号转导分子 一, 受体 Receptors,1. Receptor(受体) refers to the cellular machinery that can recognize and bind specific extracellular ligands (配体), triggering changes inside the cell. 2. Receptors are proteins, some are glycoprote
39、ins (糖蛋白), usually found on the outer surface of cells and extending through the plasma membrane, which are called membrane receptors (膜受体).,返回目录,返回主页,受体(receptor)是指存在于靶细胞膜上或细胞内能特异识别与结合生物活性分子(配体),进而引起靶细胞生物学效应的分子。绝大部分受体为蛋白质,少数为糖脂。 配体(ligand)能与受体呈特异性结合的生物活性分子, 包括细胞间信息物质、药物、维生素、毒物等。,受 体 (receptor),受体的功
40、能有三个方面: 识别与结合; 信号转导; 产生相应的生物学效应。,受体的分类、结构与功能 Classification, Structures and Functions of Receptor,(一)膜受体,这类受体是细胞膜上的结构成分,一般是糖蛋白、脂蛋白或糖脂蛋白。 多肽及蛋白质类激素、儿茶酚胺类激素、前列腺素以及细胞因子通过这类受体进行跨膜信号传递。 当配体与受体结合后,往往引起细胞膜结构和功能的改变,导致细胞内某种化学物质的浓度改变,由此触发一系列的化学和生理变化。,胞内受体(intracellular receptor) 位于细胞液或细胞核内,通常为单纯蛋白质。 此型受体主要包括类
41、固醇激素受体,如糖皮质激素受体(GR)、雌激素受体(ER)、孕激素受体(PR)、雄激素受体(AR)、盐皮质激素受体(MR);维生素D3受体(VDR)以及甲状腺激素受体(TR)。 这些激素进入细胞以后,能与特异性受体结合形成活性复合物,作用于染色体DNA,调节基因表达,从而影响细胞的物质代谢和生理活动。 Some receptors reside in cytosol or nucleus, which are called intracellular receptors (胞内受体). All of them are DNA-binding protein (either direct or
42、indirect) with regulatory activity on gene transcription.,(二)胞内受体,受体的分类、结构及功能 Classification, Structures and Functions of Receptor,1. 膜受体(Membrane receptors) (1). 配体门控离子通道 (ligand-gated ion channels, circular receptors) Ligand-gated ion channels of the plasma membrane that open and close (hence the
43、term “gating”) in response to the binding of chemical ligands (usually are neurotransmitters). These are the simplest signal transducers. The acetylcholine receptor (乙酰胆碱受体) ion channel is an example of this mechanism.,Three states of the acetylcholine receptor. Brief exposure of (a) the resting (cl
44、osed) ion channel to acetylcholine (ACh) produces (b) the excited (open) state. Longer exposure leads to (c) desensitization and channel closure.,(2). G-蛋白偶联受体(G-protein coupled receptors, GPCRs) i. GPCRs is a very large family of receptors, all with seven transmembrane helices, that are commonly ca
45、lled serpentine receptors (蛇形受体), or seven transmembrane segment (7tm) receptors (七跨膜螺旋受体). The human genome encodes more than 1,000 members of this family of receptors, specialized for transducing messages as diverse as light, smells, tastes, hormones, and neurotransmitters.,ii. GPCRs的结构(The struct
46、ure of GPCRs) 均为单链蛋白,分子中间有7个疏水段(每个疏水段由2025个氨基酸残基组成,在不同家族成员中同源),可形成跨膜螺旋。They are single polypeptide chain with seven segments in midstream that can form transmembrane helices, each of which has 2025 hydrophobic amino acid residues that homologous in different family members. N-端位于膜外侧,常连接寡糖链。C-端位于胞质侧,
47、常被棕榈酰化。N-terminal extends outwards to plasma membrane where are often attached to oligosaccharide. C-terminal reside in cytosol and often palmitoylated to help the anchoring on membrane.,GPCRs 通常含有一些保守的半胱氨酸残基,对维持受体的结构起关键作用。Some cysteine residue are highly conservative which contribute to the mainten
48、ance of right conformation. 胞外域由N-末端和3个连接环构成,是配体的结合域。胞内域与G-蛋白紧密偶联。The extracellular segments (including 3 link loops and N-terminal) compose a ligand binding domain, while intracellular segments tightly coupled with G protein.,The Structure of GPCRs (7tm receptor). (A) Schematic representation of a
49、7TM receptor showing how it passes through the membrane seven times. (B) Three-dimensional structure of rhodopsin, a 7TM receptor taking part in visual signal transduction. As the first 7TM receptor whose structure has been determined, its structure provides a framework for understanding other 7TM receptors. A linked photoreceptor molecule, retinal, is present in the position where, in at least other 7TM receptors, ligands likely bind.,Likely structure of rhodopsin (a GPCR) complexed with the G protein transducin. Rhod
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