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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
2、知的生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
3、因的翻译,所以 ,miRNA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 RR细胞对外界信号的反应是生命的特征之一。细胞对外界信号的反应是生命的特征之一。 The The ability ability
4、 of of cells cells to to receive receive and and act act on on signalssignals from from beyond the plasma membrane is fundamental to life.beyond the plasma membrane is fundamental to life. RR细菌与单细胞生物直接对环境刺激作出反应,而多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细胞生物尤其是高等生物则需要广泛的细胞间信号 交流。交流。 Bacteria Bac
5、teria and and single single cell cell organisms organisms usually usually respond respond to to environmental environmental changes changes directly. directly. While While multicellular multicellular organism organism cells cells with with different different functions functions need need to to exch
6、ange exchange a a wide wide variety variety of of intercellular intercellular signals.signals. 植物主要对生长激素及光线变化等信号起反应。植物主要对生长激素及光线变化等信号起反应。 Plant Plant cells cells respond respond to to growth growth hormones hormones and and to to variations in sunlight.variations in sunlight. 动物细胞则主要对内环境的各种变化作出反应,如动
7、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。的相互协调,以及胚胎细胞发育的精确调控等。 Animal Animal cells cells exchange exchange information information about about the the concentrations concentrations of of ions ions and and glucose glucose in in extracellular extracellula
8、r fluids, fluids, the the interdependent interdependent metabolic metabolic activities activities taking taking place place in in different different tissues, tissues, and, and, in in an an embryo, embryo, the the correct placement of cells during development. correct placement of cells during devel
9、opment. 以上的各种内外信号均由相应的信息物质以上的各种内外信号均由相应的信息物质( (分子 分子) )携携 带,可以被特定的受体识别,通过一定方式传递到带,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。这就是细胞的效应。这就是细胞的信号转导信号转导。 In In all all these these cases, cases, the the signal signal represents represents information information that that is is
10、detected detected by by specific specific receptors receptors and and converted converted to to a a cellular cellular response, response, which which always always involves involves a a chemical chemical process. process. This This conversion conversion of of information information into into a a ch
11、emical chemical change, change, signal signal transductiontransduction, , is is a a universal property of living cellsuniversal property of living cells . . RR细胞信号转导的基本过程如下:细胞信号转导的基本过程如下: The The common common process process of of signal signal transduction transduction follows follows the pathway
12、list below:the pathway list below: 特定细胞合成并分泌信号分子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信号分子通过扩散或血液循环 到达靶细胞到达靶细胞 靶细胞上的受体识别结合信号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通过一系列化学反应将信号转 导至细胞内导至细胞内 产生特定生物学效应产生特定生物学效应 some specific cells synthesize and some specific cells synthesize and secrete signal moleculessecrete signal molecul
13、es signal reach to target cells through signal reach to target cells through diffusion or blood circulation diffusion or blood circulation the specific receptor on target the specific receptor on target cells recognize and bind the signalcells recognize and bind the signal information are convert to
14、 information are convert to intracellular response via a series intracellular response via a series of chemical reactionsof chemical reactions corresponding biological effects corresponding biological effects are generatedare 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
15、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
16、 link (desmosomes, tunneling nanotubules) between the cytoplasms (metabolism of the cells is coordinated) Change in intracytoplasmic Ca+ ion concentration spreads from one cell to other in case of desmosomally linked cells Cell-cell communication: signal molecules Humoral communication between cells
17、: endocrine and paracrine contact Membrane penetrating (small, hydrophobic) molecules, cytoplasmic receptors, direct effect on gene activity Hydrophilic molecules, cell-surface receptors, intracellular signaling second messengers sophisticated signaling and signal-amplification mechanisms Definition
18、s The molecules, produced by the signaling cell (hormones, cytokines, growth factors, chemoattractants, neurotransmitters, etc.) are usually called ligands. The molecules that detect them and interact with them with high specificity and high affinity are called receptors. Receptors are located in th
19、e cytoplasm or on the plasmamembrane. The receptors we discuss today are either transcription factors or able to activate transcription factors by intracellular signaling mechanisms. Hormones Endocrine signaling: hormons are produced by endocrine glands, the extracellular signal is secreted into the
20、 blood stream, their effect is very specific Paracrine signaling molecules might circulate outside the blood vessels Autocrine factors stimulate the producing cells: in case of mitogenic factors it could lead to unlimited proliferation Signaling: 6-7 steps production of the signal, export (secretion
21、), transport, detection (receptor), intracellular signal- transduction, metabolic response, termination of the signal: decomposition of the molecule(s) participating in 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
22、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
23、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
24、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,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
25、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
26、,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: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
27、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,细胞外信号转导分子 l l 细胞外信号细胞外信号, ,又称第一信使又称第一信使, ,是指能作用到特定靶细胞并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调
28、节其生命活动的化学分子。其化学组成包括蛋白质, ,多多 肽肽, ,氨基酸及其衍生物氨基酸及其衍生物, ,脂类脂类, ,气体小分子气体小分子( (如如CO, NO)CO, NO)等。等。 Extracellular Extracellular signal, signal, also also called called first first messenger, messenger, refers refers to to the the chemical chemical molecules molecules that that secreted secreted by by speci
29、fic specific cells cells and and act act on on target target cells cells to to regulate regulate their their life. life. These These molecules molecules include include protein protein or or peptide, peptide, amino amino acids acids and and derivatives, derivatives, steroid steroid hormones, hormone
30、s, fatty fatty acid acid derivatives, and gas molecules (derivatives, and gas molecules (egeg, CO, NO)., CO, NO). 根据作用方式不同,细胞外信号主要分为四种类型:根据作用方式不同,细胞外信号主要分为四种类型: According According to to the the acting acting manner, manner, extracellular extracellular signal signal are divided into the following fo
31、ur groups:are divided into the following four groups: 1. 1. 神经递质神经递质(Neurotransmitters) (Neurotransmitters) l l Neurotransmitters Neurotransmitters are are also also called called synaptic synaptic signal signal ( (突触突触 信号信号) ). . The The arrival arrival of of an an action action potential potential
32、 triggers triggers neurotransmitter neurotransmitter release release from from the the presynapticpresynaptic cell. cell. The The neurotransmitter neurotransmitter diffuses diffuses to to the the postsynaptic postsynaptic cell, cell, binds binds to to specific specific receptors receptors in in the
33、the plasma plasma membrane, membrane, and and triggers triggers a a change change in in transmembrane transmembrane electrical electrical potential (potential ( V V mm ). ). l l 很多重要的神经递质都是由氨基酸衍生的有机胺类。很多重要的神经递质都是由氨基酸衍生的有机胺类。 Many Many important important neurotransmitters neurotransmitters are are p
34、rimary primary or or secondary secondary aminesamines, , derived derived from from amino amino acids acids in in simple simple pathways. pathways. l l 在神经递质信号传递中在神经递质信号传递中, ,信号的作用范围很小信号的作用范围很小( (微米级微米级) )。 In In neuronal neuronal signaling, signaling, the the neurotransmitter neurotransmitter may ma
35、y travel travel only only a a fraction fraction of of a a micrometermicrometer, , across across the the synaptic synaptic cleft to the next neuron in a network.cleft to the next neuron in a network. 2. 2. 激素激素(Hormones) (Hormones) l l Hormones, Hormones, also also called called endocrine endocrine s
36、ignal signal ( (内分泌信号内分泌信号 ) ), , are are synthesized synthesized by by endocrine endocrine cells cells and and released released into into the the blood blood and and carried carried to to target target cells cells throughout throughout the the body.body. l l Many Many endocrine endocrine hormones
37、hormones are are nitrogen-containing nitrogen-containing molecules molecules ( (含氮化合物含氮化合物) ), , for for example, example, epinephrineepinephrine and and thyroxinthyroxin are are amino amino acid acid derivatives, derivatives, TSHTSH and and glucagonglucagon are are peptide, peptide, insulininsulin
38、and and GHGH are are protein. protein. Another Another moiety moiety are are steroid steroid hormones hormones ( (甾体激素甾体激素) ), , such such as as sex sex hormones, corticosteroid hormone, et al.hormones, corticosteroid hormone, et al. l l 非水溶性激素通常直接与细胞内受体结合,而水溶性激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。素通
39、过结合膜受体作用。Some Some lipophilic lipophilic hormones, hormones, egeg, , steroid steroid hormones hormones and and thyroxin thyroxin can can enter enter the the cell cell and and induce induce cell cell response response through through binding binding their their intracellular intracellular receptorsre
40、ceptors. . While While other other water-soluble water-soluble hormones hormones act act on on target target cells cells through through binding binding the the membrane receptorsmembrane receptors. . l l 激素与受体的亲和力很高,只需极低的浓度激素与受体的亲和力很高,只需极低的浓度(nM(nM或更低或更低) ) 就可产生效应。就可产生效应。Hormones Hormones have have
41、 very very high high affinity affinity for for their their receptors, receptors, very very low low concentrations concentrations of of hormones hormones ( (nanomolarnanomolar or or less) less) are are sufficient sufficient to to produce produce responses in target tissues.responses in target tissues
42、. 3. 3. 局部化学介质局部化学介质(Local chemical mediators)(Local chemical mediators) l l 由特定细胞分泌,通过扩散作用于邻近的靶细胞,又称由特定细胞分泌,通过扩散作用于邻近的靶细胞,又称 为旁分泌信号。为旁分泌信号。These These signals signals usually usually actact locallylocally on on the the target target cells cells that that close close to to where where signals signal
43、s are are released released viavia diffusiondiffusion instead instead of of blood blood stream. stream. They They are are also also referred asreferred as paracrineparacrine signal signal. . l l 许多生长因子和细胞因子属于旁分泌信号。许多生长因子和细胞因子属于旁分泌信号。Many Many growth growth factorsfactors and and cytokinescytokines a
44、re are paracrineparacrine signal. signal. The The known known paracrineparacrine signals signals include include histamine, histamine, eicosanoidseicosanoids (PGs, (PGs, TXsTXs, , LTsLTs), ), interleukin, interleukin, TNFsTNFs, , CSFsCSFs, , and and somatostatinsomatostatin. . 4. 4. 气体信号气体信号(Gas sig
45、nals)(Gas signals) (1). (1). The The typical typical one one is is nitric nitric oxide oxide ( (NONO), ), and and its its origin origin and acting mechanism have been well-characterized. and acting mechanism have been well-characterized. l l NO NO is is produced produced from from argininearginine b
46、y by CaCa2+ 2+-dependent -dependent NO synthaseNO synthase, present in many mammalian tissues., present in many mammalian tissues. l l NO NO is is sufficiently sufficiently nonpolar nonpolar to to cross cross plasma plasma membranes membranes without without a a carrier. carrier. In In the the targe
47、t target cell, cell, it it binds binds to to the the heme heme group group of of guanylyl guanylyl cyclasecyclase and and activates activates cGMPcGMP production. production. In In the the heart, heart, cGMP cGMP reduces reduces the the forcefulness forcefulness of of contractionscontractions by by
48、stimulating stimulating the the ion ion pump(spump(s) ) that that expel expel CaCa2+ 2+ from from the the cytosol.cytosol. (2). Carbon monoxide (CO)(2). Carbon monoxide (CO) l l CO CO is is produced produced by by heme heme oxygenaseoxygenase and and is is toxic toxic in in high concentrations. high
49、 concentrations. l l But But the the very very low low concentrations concentrations of of COCO generated generated during during heme heme degradation degradation appears appears to to have have some some regulatory regulatory and/or and/or signaling signaling functions. functions. It It acts acts as as a a vasodilatorvasodilator, , much much the the same same as as (but (but less less potent potent than) than) nitric oxide. nitric oxide. l l Low Low levels levels of of CO CO also also have have some some regulatory regu
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