北大神经生物学课件3离子通道和神经元的电活动#高级教育

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1、Neuronal Electric Activities神经元的电活动主讲教师 刘风雨 万有神经科学研究所、神经生物学系Neuronal Electric Activities Include:Rest Potential(Chapter 3)Action Potential(Chapter 4)Local Potentials Post-Synaptic Potential Excitatory Post-Synaptic Potential Inhibitory Post-Synaptic Potential End-plate Potential Receptor PotentialCh

2、apter 3The Neuronal Membrane at Rest The CAST OF CHEMICALS Cytosol and Extracellular Fluid The Phospholipid Membrane Protein The MOVEMENT OF IONS Diffusion Electricity The IONIC BASIS OF RESTING MEMBRANE POTENTIAL Equilibrium Potential The Distribution of Ions Across the Membrane Relative Ion Permea

3、bilities of Membrane at Rest The Importance of Regulating the External Potassium Concentration CONCLUDING REMARKSCytosol and Extracellular Fluid Water:Its uneven distribution of electrical charge,so H2O is a polar molecule Ions:Salt dissolves readily in water because the charged portions of the wate

4、r molecule have a stronger attraction for the ions than they have for each otherThe Phospholipid Membrane(磷脂膜)The lipids of the neuronal membrane forming:l a barrier to water-soluble ions l a barrier to water头端-极性磷酸盐-亲水尾端-非极性碳氢化合物-疏水5Protein These proteins provide routes for ions to cross the neuron

5、al membrane.The resting and action potentials depend on special proteins that span the phospholipid bilayer.Protein Amino AcidsThe Peptide Bond(肽键)and a Polypeptide(多肽)Figure 3.6 Protein StructureThe primary structureThe secondary structureThe tertiary structureThe quaternary structureEach of the di

6、fferent polypeptides contributing to a protein with quaternary structure is called a subunit(亚基).Channel Proteins Channel protein is suspended in a phospholipid bilayer,with its hydrophobic(疏水的)portion inside the membrane hydrophilic(亲水的)ends exposed to the watery environments on either sideFigure 3

7、.7 A Membrane Ion Channel10Two Properties of Ion Channels Ion selectivity(离子选择性)The diameter of the pore The nature of the R groups lining it Gating(门控特性)Channels with this property can be opened and closed-gated by changes in the local microenvironment of the membraneIon Pumps(离子泵)Ion pumps are enz

8、ymes that use the energy released by the breakdown of ATP to transport certain ions across the membraneChapter 3The Neuronal Membrane at Rest THE CAST OF CHEMICALS Cytosol and Extracellular Fluid The Phospholipid Membrane Protein THE MOVEMENT OF IONS Diffusion Electricity THE IONIC BASIS OF RESTING

9、MEMBRANE POTENTIAL Equilibrium Potential The Distribution of Ions Across the Membrane Relative Ion Permeabilities of Membrane at Rest The Importance of Regulating the External Potassium Concentration CONCLUDING REMARKSTHE MOVEMENT OF IONS A channel across a membrane is like a bridge across a river.A

10、n open channel A net movement of ions across the membrane.Ion movement requires that external forces be applied to drive ions across.Two factors influence ion movement through channels:Diffusion(扩散)Electricity(电势差)Diffusion Temperature-dependent random movement of ions and molecules tends to distrib

11、ute the ions evenly throughout the solution so that there is a net movement of ions from regions of high concentration to regions of low concentration.This movement is called diffusion(扩散).A difference in concentration is called a concentration gradient(浓度梯度).15Figure 3.8 Diffusion Driving ions acro

12、ss the membrane by diffusion happens when The membrane possesses channels permeable to the ions There is a concentration gradient across the membraneElectricity Another way to induce a net movement of ions in a solution is to use an electrical field(电场),because ions are electrically charged particle

13、s.Opposite charges attract and like charges repel.Figure 3.9 The movement of ions influenced by an electrical fieldOpposite charges attract and like charges repelElectricity Two important factors determine how much current(I)will flow:Electrical potential(V,电势)Electrical conductance(g,电导)Electrical

14、conductance Electrical resistance(电阻,R=1/g)Ohms law:I=gVFigure 3.10 Electrical current flow across a membrane Driving an ion across the membrane electrically requires The membrane possesses channels permeable to the ions There is a electrical potential difference across the membrane20Diffusion and E

15、lectricity Electrical charged ions in solution on either side of the neuronal membrane.(带电离子溶解在细胞膜两侧的溶液中)Ions can cross the membrane only by protein channel.(离子必须通过离子通道实现跨膜运动)The protein channels can be highly selective for specific ions.(离子通道对离子具有高度的选择性)The movement of any ion through channel depen

16、ds on the concentration gradient and the difference in electrical potential across the membrane.(离子的跨膜运动依赖于膜两侧的浓度梯度和电位差)Chapter 3The Neuronal Membrane at Rest The CAST OF CHEMICALS Cytosol and Extracellular Fluid The Phospholipid Membrane Protein The MOVEMENT OF IONS Diffusion Electricity The IONIC

17、BASIS OF RESTING MEMBRANE POTENTIAL Equilibrium Potential The Distribution of Ions Across the Membrane Relative Ion Permeabilities of Membrane at Rest The Importance of Regulating the External Potassium Concentration CONCLUDING REMARKS The membrane potential(膜电位)is the voltage across the neuronal me

18、mbrane at any moment,represented by the symbol mV.Microelectrode (微电极)and mV measurementTHE IONIC BASIS OF THE RESTING MEMBRANE POTENTIAL(静息电位)Establishing Equilibrium Potential(平衡电位)Figure 3.12 Establishing equilibrium in a selectively permeable membraneNo potential differenceVm=0 mVThe diffusional

19、 force=The electrical forceVm=-80 mV20:1Equilibrium potentials The electrical potential difference that exactly balances an ionic concentration gradient is called an ionic equilibrium potential,or simply equilibrium potential (当离子移动所产生的电位差和离子移动所造成的浓度势能差平衡时，不再有离子的净移动，这时膜两侧的电位差称为离子的平衡电位)Generating a s

20、teady electrical potential difference across a membrane requires An ionic concentration gradient Selective ionic permeability25Before moving on to the situation in real neurons,four important points should be made:1.Large changes in membrane potential are caused by minuscule changes in ionic concent

21、rations (仅需要微小的离子浓度改变就可以引起膜电位大幅度的变化)100 mM99.99999mMVm=-80 mVVm=0 mVBefore moving on to the situation in real neurons,four important points should be made:2.The net difference in electrical charge occurs at the inside and outside surfaces of the membrane (膜内外两侧电荷的不同仅仅分布于膜的内外侧面，而不是分布于整个细胞的内外液)Figure

22、3.13(5 nm)Before moving on to the situation in real neurons,four important points should be made:3.Ions are driven across the membrane at a rate proportional to the difference between the membrane potential and the equilibrium potential(离子的跨膜速率与膜电位和平衡电位的差值成正比).Net movement of K+occurs as the membran

23、e potential differed from the equilibrium potential.This difference (Vm-Eion)is called the ionic driving force(离子驱动力).4.If the concentration difference across the membrane is known for an ion,an equilibrium potential can be calculated for that ion(根据某离子膜两侧浓度的差值可以计算该离子的平衡电位).Na+Equilibrium PotentialF

24、igure 3.14 Another example establishing equilibrium in a selectively permeable membraneThe Nernst Equation The exact value of an equilibrium potential in mV can be calculated using the Nernst equation,which takes into consideration:The charge of the ion The temperature The ratio of the external and

25、internal ion concentrationsPage 64.Box 3.2.Mark F.Bear,et al.ed.Neuroscience:Exploring the Brain.2nd edition.EK=2.303 log ZFRTioKK30Figure 3.15Figure 3.15Approximate ion concentrations on either side of a neuronal membrane.Relative Ion Permeabilities of Membrane at Rest The resting membrane permeabi

26、lity is forty times greater to K+than to Na+The resting membrane potential is 65mVThe Distribution of Ions Across the Membrane Ionic concentration gradients are established by the actions of ions pumps in the neuronal membrane (膜内外两侧的离子浓度梯度的形成依赖于 离子泵的活动)Two important ion pumps:The sodium-potassium p

27、ump(钠钾泵)is an enzyme that breaks down ATP in the presence of internal Na+.The calcium pump(钙泵)is an enzyme that actively transports Ca2+out of the cytosol across the cell membrane.Figure 3.16Figure 3.16 The sodium-potassium pump.K+K+Na+Na+Figure 4.4Membrane currents and conductances35 The most potas

28、sium channels have four subunits that are arranged like the staves of a barrel to form a pore Of particular interest is a region called the pore loop(孔袢孔袢),which contributes to the selectivity filter that makes the channel permeable mostly to K+ions.The wide world of potassium channelsFigure 3.18Fig

29、ure 3.18A view of the atomic structure of the potassium channel poreThe importance of regulating the external potassium concentrationIncreasing extracellular potassium depolarizes neuronsFigure 3.19The dependence of membrane potential on external potassium concentration.550-65-17Two protective mecha

30、nisms in the brain Blood-brain barrier(血脑屏障)limits the movement of potassium(and other blood-borne substances)into the extracellular fluid of the brain Glia,particularly astrocytes,take up extracellular K+whenever concentrations rise,as they normally do during periods of neural activity.Figure 3.20F

31、igure 3.20Potassium spatial buffering by astrocytes.When brain K+o increases as a result of local neural activity,K+enters astrocytes via membrane channels.The extensive network of astrocytic processes helps dissipate the K+over a large area.40Chapter 3The Neuronal Membrane at Rest The CAST OF CHEMI

32、CALS Cytosol and Extracellular Fluid The Phospholipid Membrane Protein The MOVEMENT OF IONS Diffusion Electricity The IONIC BASIS OF RESTING MEMBRANE POTENTIAL Equilibrium Potential The Distribution of Ions Across the Membrane Relative Ion Permeabilities of Membrane at Rest The Importance of Regulat

33、ing the External Potassium Concentration CONCLUDING REMARKSNeuronal Electric Activities Include:Rest Potential(Chapter 3)Action Potential(Chapter 4)Local PotentialsPost-Synaptic Potential Excitatory Post-Synaptic Potential Inhibitory Post-Synaptic PotentialEnd-plate PotentialReceptor PotentialChapte

34、r 4 The Action Potential PROPERTIES OF THE ACTION POTENTIAL The Ups and Downs of an Action Potentials Generation of an Action Potential The Generation of Multiple Action Potentials THE ACTION POTENTIAL IN THEORY Membrane Currents and Conductances The Ins and Outs of Action Potential THE ACTION POTEN

35、TIAL IN REALITY The Voltage-Gated Sodium Channel Voltage-Gated Potassium Channels Putting the Pieces Together ACTION POTENTIAL CONDUCTION Factor influencing conduction velocity ACTION POTENTIALS,AXONS,AND DENDRITES CONCLUDING REMARKSMethods of Recording Action Potentials细胞内记录细胞外记录示波器The Ups and Down

36、s of an Action Potentials上升支（去极化）下降支（复极化）超射超 极 化 激 活后电位2 ms-65 mV45Generation of an action potential The perception of sharp pain when a thumbtack enters your foot is caused by the generation of action potentials in certain nerve fibers in the skin:The thumbtack enters the skin(图钉扎入皮肤)The membrane o

37、f the nerve fibers in the skin is stretched (感觉神经纤维的细胞膜被牵拉)Na+-permeable channels open.The entry of Na+depolarizes the membrane(Na+通道打开，细胞膜产生去极化)The critical level of depolarization that must be crossed in order to trigger an action potential is called threshold(阈电位).Action potential are caused by d

38、epolarization of the membrane beyond threshold.The depolarization that causes action potential arises in different ways in different neurons(引起去极化的不同方式):1.Caused by the entry of Na+through specialized ion channels that sensitive to membrane stretching(膜的牵拉)2.In interneurons,depolarization is usually

39、 caused by Na+entry through channels that are sensitive to neurotransmitters (神经递质的释放)released by other neurons3.In addition to these natural routes,neurons can be depolarized by injecting electrical current(注入电流)through a microelectrode,a method commonly used by neuroscientists to study action pote

40、ntials in different cells.Applying increasing depolarization to a neuron has no effect until it crosses threshold,and then“pop”one action potential.For this reason,action potentials are said to be“all-or-none”(全或无现象).The generation of multiple action potentials Continuous depolarizing current Many a

41、ction potentials in succession注入电流The firing frequency of action potentials reflects the magnitude of the depolarizing current(频率反应去极化电流的大小)This is one way that stimulation intensity is encoded in the nervous system(中枢神经系统编码刺激强度的一种方式)Though firing frequency increases with the amount of depolarizing

42、current,there is a limit to the rate at which a neuron can generate action potentials.Absolute refractory period(绝对不应期)Once an action potential is initiated,it is impossible to initiate another for about 1 ms (动作电位产生后1 ms,不可能产生别的动作电位)Relative refractory period(相对不应期)The amount of current required to

43、 depolarize the neuron to action potential threshold is elevated above normal (绝对不应期之后的几个ms,需要比正常更大的阈电流才能爆发动作电位)50Chapter 4 The Action Potential PROPERTIES OF THE ACTION POTENTIAL The Ups and Downs of an Action Potentials Generation of an Action Potential The Generation of Multiple Action Potentials

44、 THE ACTION POTENTIAL IN THEORY Membrane Currents and Conductances The Ins and Outs of Action Potential THE ACTION POTENTIAL IN REALITY The Voltage-Gated Sodium Channel Voltage-Gated Potassium Channels Putting the Pieces Together ACTION POTENTIAL CONDUCTION Factor influencing conduction velocity ACT

45、ION POTENTIALS,AXONS,AND DENDRITES CONCLUDING REMARKSTHE ACTION POTENTIAL IN THEORY Depolarization of the cell during the action potential is caused by the influx of sodium ions across the membrane (去极化是钠离子内流造成的)Repolarization is caused by the efflux of potassium ions (复极化是钾离子外流造成的)The Ins and Outs

46、of Action Potential The rising phase A very large driving force on Na+(-80-62)mV=-142mV The membrane permeability to Na+K+Depolarization of the membrane beyond threshold,membrane sodium channels opened.This would allow Na+to enter the neuron,causing a massive depolarization until the membrane potent

47、ial approached ENa.The falling phase The dominant membrane ion permeability to K+K+flow out of the cell until the membrane potential approached EK.The ins and outs and ups and downs of the action potential in an ideal neuron is shown as below:(Fig 4.5)55Chapter 4 The Action Potential PROPERTIES OF T

48、HE ACTION POTENTIAL The Ups and Downs of an Action Potentials Generation of an Action Potential The Generation of Multiple Action Potentials THE ACTION POTENTIAL IN THEORY Membrane Currents and Conductances The Ins and Outs of Action Potential THE ACTION POTENTIAL IN REALITY The Voltage-Gated Sodium

49、 Channel Voltage-Gated Potassium Channels Putting the Pieces Together ACTION POTENTIAL CONDUCTION Factor influencing conduction velocity ACTION POTENTIALS,AXONS,AND DENDRITES CONCLUDING REMARKSVoltage clamp(电压钳)proves the above theory:The Voltage-Gated Sodium Channel(电压门控的钠离子通道)The protein forms a p

50、ore in the membrane that is highly selective to Na+ions(对Na+具有高度的选择性).The pore is opened and closed by changes in the electrical potential of the membrane(Na+通道的开放和关闭具有电压依从性).Sodium channel structure(Na+通道的结构)Created from a single long polypeptide Has 4 distinct domains,numbered I-IV.The four domain

51、s are believed to clump together to form a pore between them Each domain consists of 6 transmembrane alpha helices,numbered S1-S6 The channel has pore loops that are assembled into a selectivity filter60Figure 4.6Structure of the voltage-gated sodium channel(a)How the sodium channel polypeptide chai

52、n is believed to be woven into the membrane.The molecule consists of four domains,I-IV.Each domain consists of 6 alpha helices,which pass back and forth across the membraneFigure 4.6(b)An expanded view of one domain showing the voltage sensor of alpha helix S4 and the pore loop(red),which contribute

53、s to the selectivity filter(c)A view of the molecule showing how the domains may arrange themselves to form a pore between them.电压感受器Figure 4.7When the membrane is depolarized to threshold,the molecule twists into a configuration that allows the passage of Na+through the pore.The voltage sensor resi

54、des in segment S4 of the molecule.In this segment,positively charged amino acid residues are regularly spaced along the coils of the helix.Thus,the entire segment can be forced to move by changing the membrane potential.Depolarization pushes S4 away from the inside of the membrane,and this conformat

55、ional change in the molecule causes the gate to open.The patch-clamp(膜片钳)Method-40 mV65Functional properties of the sodium channel(Na+通道的功能)1.They open with little delay2.They stay open for about 1 ms and then close(inactivate)3.They cannot be opened again by depolarization until the membrane potent

56、ial returns to 65 mV关闭开放失活去失活Functional properties of the sodium channelFigure 4.9(c)A model for how changes in the conformation of the sodium channel protein might yield its functional properties.1.The closed(关闭)channel;2.Opens(开放)upon membrane depolarization;3.Inactivation(失活)occurs when a globula

57、r portion of the protein swings up and occludes the pore;4.Deinactivation(去失活)occurs when the globular portion swings away and the pore closes by movement of the transmembrane domains关闭开放失活去失活Toxins on the sodium channel Tetrodotoxin(TTX,河豚毒素)and saxitoxinChannel-blocking toxin Batrachotoxin,veratri

58、dine and aconitineOpen the channels inappropriatelyOpen at more negative potentialsOpen much longer than usualPutting the Pieces Together(page 89)Threshold Rising phase Overshoot Falling phase Undershoot Absolute refractory period Relative refractory periodFigure 4.10 The molecular basis of the acti

59、on potential70Chapter 4 The Action Potential PROPERTIES OF THE ACTION POTENTIAL The Ups and Downs of an Action Potentials Generation of an Action Potential The Generation of Multiple Action Potentials THE ACTION POTENTIAL IN THEORY Membrane Currents and Conductances The Ins and Outs of Action Potent

60、ial THE ACTION POTENTIAL IN REALITY The Voltage-Gated Sodium Channel Voltage-Gated Potassium Channels Putting the Pieces Together ACTION POTENTIAL CONDUCTION Factor influencing conduction velocity ACTION POTENTIALS,AXONS,AND DENDRITES CONCLUDING REMARKSFigure 4.11 Action potential conductionFigure 4

61、.11Action potential conduction.The entry of positive charge during the action potential causes the membrane just ahead to depolarize to threshold(已经兴奋的膜部分通过局部电流“刺激”了未兴奋的膜部分，使之出现动作电位)An action potential propagates in one direction An action potential can be generated by depolarization at either end o

62、f the axon and therefore propagate in either directionFactors Influencing Conduction Velocity Action potential conduction velocity increases with increasing axonal diameter (轴突的直径)Axonal size and the number of voltage-gated channels in the membrane also affect axonal excitability (轴突上钠离子通道的密度).Tempe

63、rature (温度)Myelin and Saltatory Conduction Myelin(髓鞘)Schwann cells in the peripheral nervous system Oligodendroglia in the central nervous system Voltage-gated sodium channels are concentrated in the membrane of the nodes of Ranvier(郎飞结)In myelinated axones,action potentials skip from node to node(S

64、altatory conduction 跳跃式传导)Myelin and Saltatory ConductionIn myelinated axones,action potentials skip from node to node(Saltatory conduction)75Chapter 4 The Action Potential PROPERTIES OF THE ACTION POTENTIAL The Ups and Downs of an Action Potentials Generation of an Action Potential The Generation o

65、f Multiple Action Potentials THE ACTION POTENTIAL IN THEORY Membrane Currents and Conductances The Ins and Outs of Action Potential THE ACTION POTENTIAL IN REALITY The Voltage-Gated Sodium Channel Voltage-Gated Potassium Channels Putting the Pieces Together ACTION POTENTIAL CONDUCTION Factor influen

66、cing conduction velocity ACTION POTENTIALS,AXONS,AND DENDRITES CONCLUDING REMARKSSpike-initiation zone Only membrane that contains voltage-gated sodium channels is capable of generating action potential.Voltage-gated sodium channels The axons The dendritesThe axons The cell bodies The part of the neuron where an axon originates from the soma,the axon hillock(轴丘),is often also called the spike-initiation zone(动作电位起始点).Figure 4.14 Membrane protein specify the function of different parts of the neu