1、第八章钙离子与信号转导1第八章第八章 钙离子与信号转导钙离子与信号转导Calcium and Signal Transduction Calcium a life and death signallife and death:死活|生与死|生死攸关第八章钙离子与信号转导2Calcium BiologyTransmitter ReleaseNeuralPlasticityCell GrowthCell DeathMuscleContractionGeneRegulationHormone SecretionProteinPhosphorylation Ca2+第八章钙离子与信号转导3No oth
2、er mineral is capable of performing as many biological functions as is calcium.Calcium is involved in almost every biological function.Calcium atom第八章钙离子与信号转导4Why Calcium,not other ions?IntroductionCalcium(orange)胞内外、钙库内外有胞内外、钙库内外有 钙离子的特性使其钙离子的特性使其Ca2+TargetmMmM0.110 m mM第八章钙离子与信号转导5Calcium in the b
3、ody机体总钙机体总钙99分布在骨骼分布在骨骼0.5在牙在牙0.5在软组织（细胞内钙）在软组织（细胞内钙）0.02在血浆在血浆第八章钙离子与信号转导6Calcium in the blood血液中钙血液中钙99%-血浆血浆蛋白质结合钙（蛋白质结合钙（46%)有机酸结合钙有机酸结合钙-复合钙复合钙离子钙（离子钙（48%）1%-血细胞中血细胞中The ionized form of calcium in the serum is critical to healthy physiologic function.第八章钙离子与信号转导7Calcium in the cell细胞内钙细胞内钙99.9%
4、-结合钙结合钙0.1%游离钙在胞内游离钙在胞内 浓度浓度0.1 m mmol/L5存在于细胞膜，细胞浆内结合钙占存在于细胞膜，细胞浆内结合钙占0.5，作为第二信使的游离钙仅占细胞内钙的作为第二信使的游离钙仅占细胞内钙的0.005。细胞内钙细胞内钙50存存在于胞核内在于胞核内44存在于胞内钙库（线粒体和内质网）存在于胞内钙库（线粒体和内质网）内质网游离钙浓度也只有内质网游离钙浓度也只有0.5 m mmol/L第八章钙离子与信号转导8机体对血浆钙的总体调节：机体对血浆钙的总体调节：The parathyroid hormone（PTH，甲状旁腺素），甲状旁腺素）regulate ionized c
5、alcium and determine its （再吸收）（再吸收）into bone,absorption from the GI mucosa（粘膜）（粘膜）,and excretion in urine（尿）（尿）and stool（粪）（粪）.第八章钙离子与信号转导9细胞的钙转移系统细胞的钙转移系统内质网的钙转移（灵敏而快速）内质网的钙转移（灵敏而快速）线粒体的钙转移（大容量而持久）线粒体的钙转移（大容量而持久）质膜（细胞膜）的钙转移质膜（细胞膜）的钙转移1.质膜（细胞膜）的钙转移系统质膜（细胞膜）的钙转移系统钙泵：钙泵：，起，起作用作用Na+/Ca2+交换器：交换器：低亲和力高容量
6、低亲和力高容量，起，起作用作用离子通道：离子通道：，激动剂，激动剂-受体门控性，机械操纵型受体门控性，机械操纵型泵与通道的区别？泵与通道的区别？第八章钙离子与信号转导102.内质网的钙转移（灵敏而快速）内质网的钙转移（灵敏而快速）3.线粒体的钙转移（大容量而持久）线粒体的钙转移（大容量而持久）单向转运体（单向转运体（uniportor）：转运钙进入线粒体：转运钙进入线粒体 通过通过交换形式运送钙出线粒体交换形式运送钙出线粒体耗能较小（浓度差小），效率高耗能较小（浓度差小），效率高IP3受体钙通道，受体钙通道，Ryanodine受体钙通道受体钙通道第八章钙离子与信号转导11细胞内钙库：细胞内钙库
7、：，而是因为，而是因为。降低游离钙浓度，防止高钙损伤降低游离钙浓度，防止高钙损伤可快速解离，使可快速解离，使Ca2+信号准确信号准确 迅速迅速第八章钙离子与信号转导12PMCA:Plasma membrane Ca2+ATPaseSERCA:sarco/endoplasmic reticulum Ca2+-ATPase compartment of calcium in the cell第八章钙离子与信号转导13Calcium a life and death signal第八章钙离子与信号转导14 A long-standing question in cell signaling is h
8、ow Ca2+,with its abundant and varied intracellular targets,is able to achieve specificity and activates only a subset of those targets.第八章钙离子与信号转导15This incredible v arises through the use of a Ca2+-signalling tool kit,whereby the ion can act in the various contexts of 的变化在细胞功能的调节中有重的变化在细胞功能的调节中有重要的
9、作用。要的作用。Determination of the versatility of Ca2+signaling 第八章钙离子与信号转导16Space two,external and internal Ca2+events the basic building blocks(预制件预制件)of Ca2+signaling,Ca2+sparks,Ca2+puffs,Ca2+blips第八章钙离子与信号转导17Elementary events generate localized concentrations of Ca2+that can activate many processes:(
10、1)export of cellular material (2)opening of K+channels,(3)metabolism in the mitochondria (4)entering the nucleus and activating transcription第八章钙离子与信号转导18The activity of neighboring cells within a tissue can be coordinated by that spreads from one cell to the next.第八章钙离子与信号转导19Ca2+sparks-elementary
11、Ca2+release events underlying ECC单个心肌细胞兴奋时钙离子释放产生的钙火花单个心肌细胞兴奋时钙离子释放产生的钙火花ECC:Excitation-Contraction Coupling第八章钙离子与信号转导20 5m 255 0 Distribution of calcium spark in ASMC2D scanning image of calcium sparkIllustration of line scan position动脉平滑肌细胞动脉平滑肌细胞(ASMC)兴奋产生的钙火花兴奋产生的钙火花第八章钙离子与信号转导21Spontaneous rec
12、ording of calcium spark and STOCCalcium sparkSTOCTop.line scanning image;Middle:change of fluorescence amplitude(F/F0)with time course;Bottom:corresponding change in STOC with fluorescence amplitude.pA 100 2.0 1.0 F/F0 200ms 0 STOC:Spontaneous transient outward current,自发瞬时外向电流自发瞬时外向电流第八章钙离子与信号转导22E
13、lementary Ca2+release events(known as Ca2+puffs and Ca2+blips)recorded from a single endothelial cell.第八章钙离子与信号转导23Time Cells avoid death either by usingsignals or,more usually,by delivering the signals as brief Cells use frequency modulation to vary the intensity and nature of the physiological out
14、put.第八章钙离子与信号转导24 High frequent Ca2+sparks can relax smooth muscle cells Frequency of Ca2+oscillation determines the mode of gene transcription第八章钙离子与信号转导25钙离子浓度的升高增加钙振荡的幅度和频率钙离子浓度的升高增加钙振荡的幅度和频率第八章钙离子与信号转导26钙振荡与否钙振荡与否影响基因的影响基因的表达表达第八章钙离子与信号转导27细胞内钙离子浓度和钙振荡对基因表达的不同影响细胞内钙离子浓度和钙振荡对基因表达的不同影响第八章钙离子与信号转导2
15、8Amplitude Different genes can be activated by varying the amplitude of Ca2+signals.Oscillations of the intracellular calcium concentration are known as a way of signal transduction between cells.Changes in amplitude and frequency of these oscillations can induce cell proliferation or the growth of
16、synapses in neuronal networks.第八章钙离子与信号转导29Fertilization and development （受精与发育）（受精与发育）In mammals,life begins at fertilization when the sperm interacts with the egg to trigger a Ca2+oscillation that persists for several hours.This prolonged period of repetitive Ca2+pulses triggers the developmental
17、program by stimulating the enzymatic machinery involved in the cell-division cycle.Significance of Ca2+signaling第八章钙离子与信号转导30EvidencesIn amphibians and zebrafish it is thought to help specify which cells will form structures at the top(dorsal)or the bottom(ventral)part of the embryo.In development o
18、f the heart,the Ca2+-dependent nuclear factor of activated T cells(NF-AT)helps to form the cardiac septum and valves.Spontaneous Ca2+transients with different frequencies are responsible for various aspects of differentiation in developing amphibian neurons.As embryos grow and groups of cells differ
19、entiate to perform specialized functions,Ca2+signaling contributes to body polarity and pattern formation.第八章钙离子与信号转导31Ca2+signalling during six stages of zebrafish development第八章钙离子与信号转导322.Cell proliferation（细胞增殖）（细胞增殖）A prolonged period of Ca2+signaling is an important growth signal for many cell
20、s,e.g.,tumor,cardiac hypertrophy,angiogenesis.第八章钙离子与信号转导33Control of cardiac gene transcription by calcium/calmodulin dependent signaling.第八章钙离子与信号转导34Interplay among AA,NO and calcium in endothelial cellsAA：花生四烯酸：花生四烯酸第八章钙离子与信号转导353.Cell deathNecrosis:Very high concentrations of Ca2+can lead to th
21、e disintegration of cells(necrosis)through the activity of Ca2+-sensitive protein-digesting enzymes.Apoptosis:Mitochondrial Ca2+plays a critical role.第八章钙离子与信号转导36The roles of calcium and cytochrome c as inter-organellar messengers in apoptosis.Nature Cell Biology 5,1041-1043(2003)第八章钙离子与信号转导37Neuro
22、n Ca2+signaling第八章钙离子与信号转导38第八章钙离子与信号转导39Future Challenge Compartment of Ca2+signaling:Nuclear,Mitochondria Crosstalk between Ca2+signaling and ROS signaling第八章钙离子与信号转导40钙离子发挥作用的重要伙伴：钙结合蛋白钙离子发挥作用的重要伙伴：钙结合蛋白Calcium binding proteinCa2+-signaling is mediated through several Ca2+-binding proteins,including calmodulin(CaM)and protein kinase C(PKC).重点：重点：Calmodulin 第八章钙离子与信号转导41第八章钙离子与信号转导42第八章钙离子与信号转导43第八章钙离子与信号转导44第八章钙离子与信号转导45
