北大神经生物学3离子通道和神经元的电活动课堂

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 Potent

2、ial,Chapter 3,The 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

3、 Permeabilities of Membrane at Rest,The Importance of Regulating the External Potassium,Concentration,CONCLUDING REMARKS,Cytosol and Extracellular Fluid,Water,Its uneven distribution,of electrical charge, so,H,2,O is a polar molecule,Ions,Salt dissolves readily in,water because the,charged portions

4、of the,water molecule have a,stronger attraction for,the ions than they have,for each other,The Phospholipid Membrane,磷脂膜,The lipids of the neuronal,membrane forming,a barrier to water-soluble ions,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,5,Protein,These proteins provide,routes for ions to cros

5、s,the neuronal membrane,The resting and action,potentials depend on,special proteins that,span the phospholipid,bilayer,Protein,Amino Acids,The Peptide Bond,肽键,and,a Polypeptide,多肽,Figure 3.6 Protein Structure,The primary structure,The secondary structure,The tertiary structure,The quaternary struct

6、ure,Each of the different 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 ei

7、ther side,Figure 3.7 A Membrane,Ion Channel,10,Two 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,membrane,Ion Pumps,

8、离子泵,Ion pumps are enzymes that use,the energy released by the,breakdown of ATP to transport,certain ions across the membrane,Chapter 3,The Neuronal Membrane at Rest,THE CAST OF CHEMICALS,Cytosol and Extracellular Fluid,The Phospholipid Membrane,Protein,THE MOVEMENT OF IONS,Diffusion,Electricity,THE

9、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 Regulating the External Potassium,Concentration,CONCLUDING REMARKS,THE MOVEMENT OF IONS,A channel across a membrane is like a

10、 bridge,across a river,An 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 mo

11、lecules tends to distribute 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,15,Figure 3.8 Diff

12、usion,Driving ions across the membrane by diffusion,happens when,The membrane possesses channels,permeable,to,the ions,There is a,concentration gradient,across the,membrane,Electricity,Another way to induce a net movement of ions,in a solution is to use,an electrical field,电场,because ions are electr

13、ically charged particles,Opposite charges attract and like charges repel,Figure 3.9,The movement of,ions influenced by,an electrical field,Opposite,charges,attract,and,like,charges,repel,Electricity,Two important factors determine how,much,current (I,will flow,Electrical potential,V,电势,Electrical co

14、nductance,g,电导,Electrical conductance,Electrical resistance,电阻,R=1/g,Ohms law: I = gV,Figure 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

15、 the membrane,20,Diffusion and Electricity,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

16、any ion through channel depends 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 3,The Neuronal Membrane at Rest,The CAST OF CHEMICALS,Cytosol and Extracellular Fluid,The Phospholipid Membrane,Protein,The MOVEMENT OF IONS,

17、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 Regulating the External Potassium,Concentration,CONCLUDING REMARKS,The,membrane,potential,膜电位,is th

18、e voltage,across the neuronal,membrane at any,moment,represented by the,symbol,mV,Microelectrode,微电极,and mV,measurement,THE 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 membrane,No potential

19、 difference,V,m,0 mV,The diffusional force = The electrical force,V,m,80 mV,20,1,Equilibrium 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

20、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 steady electrical potential,difference across a membrane requires,An ionic concentration gradient,Selective ionic permeability,25,Before moving on to the situation in real,neurons, four important points should be made,1,Large changes in,membrane potential,ar

21、e caused by,minuscule changes,in ionic,concentrations,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,mM,99.99999,mM,V,m,80 mV,V,m,0 mV,Before 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

22、,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,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

23、速率与膜电位和平衡电位的差值成正比,Net movement of K,occurs as the membrane potential,differed from the equilibrium potential. This difference,V,m,E,ion,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 th

24、at 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 Potential,Figure 3.14 Another example establishing equilibrium in a selectively permeable membrane,The Nernst Equation,The exact value of,an equilibrium potential,in mV can,be calculated using,the Nernst equation,which,takes into consideration,The cha

25、rge of the ion,The temperature,The ratio of the external and internal ion concentrations,Page 64. Box 3.2,Mark F. Bear, et al. ed. Neuroscience: Exploring the,Brain. 2,nd,edition,E,K,2.303,log,ZF,RT,i,o,K,K,30,Figure 3.15,Figure 3.15,Approximate ion,concentrations on,either side of a,neuronal,membra

26、ne,Relative Ion Permeabilities of Membrane at Rest,The resting membrane,permeability is,forty times,greater to K,than to Na,The resting membrane,potential is,65mV,The Distribution of Ions Across the Membrane,Ionic,concentration gradients,are established,by the actions of,ions pumps,in the neuronal,m

27、embrane,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 pump,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 Ca,2,out of the cytosol across,the cell membrane,Figure 3.16,Figure 3.16 The sodium-po

28、tassium pump,K,K,Na,Na,Figure 4.4,Membrane currents,and conductances,35,The most potassium,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,which contributes to,the selectivity filter,that makes the ch

29、annel,permeable mostly to K,ions,The wide world of potassium channels,Figure 3.18,Figure 3.18,A view of the,atomic,structure of,the potassium,channel pore,The importance of regulating the external,potassium concentration,Increasing extracellular potassium depolarizes neurons,Figure 3.19,The dependen

30、ce of,membrane,potential on,external potassium,concentration,5,50,65,17,Two protective mechanisms 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,

31、whenever concentrations rise, as they,normally do during periods of neural activity,Figure 3.20,Figure 3.20,Potassium,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

32、,helps dissipate the,K,over a large area,40,Chapter 3,The 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

33、of Ions Across the,Membrane,Relative Ion Permeabilities of Membrane at,Rest,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,Cha

34、pter 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 PO

35、TENTIAL 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,Methods of Recording Action Potentials,细胞内记录,细胞外记录,示波器,The Ups and Downs of an Action Pote

36、ntials,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,mV,45,Generation 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 of the nerve f

37、ibers 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,The depolarization that causes,action potential arises in different,ways in dif

38、ferent 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 caused by,Na,entry through channels that are sensitive to,neurotransmitters,神经递质的释放,released by other neurons,3. In additio

39、n 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 potentials in,different cells,The generation of multiple action potentials,Continuous depolarizing current,Many action potent

40、ials 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,Though firing frequency increases with,the amount of depolarizing current, there,is a

41、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 depolarize the,ne

42、uron 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,50,Chapter 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 POTE

43、NTIAL 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,ACTION POTENTIALS,

44、AXONS, AND,THE 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 of Action Potential,The rising phase,A very

45、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 potential,approached,E,Na,The falling phase,The d

46、ominant membrane ion,permeability to K,K,flow out of the cell until the membrane potential,approached,E,K,The ins and outs and ups and downs of,the action potential in an ideal neuron is,shown as below: (Fig 4.5,55,Chapter 4 The Action,Potential,PROPERTIES OF THE ACTION POTENTIAL,The Ups and Downs o

47、f 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 Channel,Voltage-Gated Potassium Channe

48、ls,Putting the Pieces Together,ACTION POTENTIAL CONDUCTION,Factor influencing conduction velocity,ACTION POTENTIALS, AXONS, AND,Voltage 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 pore in the,membrane that is highly,selective to,Na,ions,对,Na,具有高度

49、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 domains are believed to,clump together to form a pore between,them,Ea

50、ch domain consists of,6,transmembrane alpha helices,numbered S1-S6,60,Figure 4.6,Structure of the voltage-gated sodium channel,a) How the sodium channel polypeptide chain is believed to,be woven into the membrane. The molecule consists of,four,domains,I-IV. Each domain consists of,6 alpha helices,wh

51、ich,Figure,4.6,b) An expanded,view of one,domain showing,the voltage,sensor of,alpha,helix S4,and,the,pore loop,red,which,contributes to,the selectivity,filter,c) A view of the,molecule,showing how,the domains,电压感受器,Figure,4.7,When the membrane is depolarized to threshold, the molecule twists into a

52、,configuration that allows the passage of Na+ through the pore,The voltage sensor resides 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,po

53、tential. Depolarization pushes S4 away from the inside of the membrane,The patch-clamp,膜片钳,Method,40,mV,65,Functional properties of the sodium channel,Na,通道的功能,1,They open with little,delay,2,They stay open for about,1 ms,and then close,inactivate,3,They cannot be opened again by depolarization unti

54、l,关闭,开放,失活,去失活,Functional properties of the sodium channel,Figure 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 globular portion o

55、f 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,关闭,开放,失活,去失活,Toxins on the sodium,channel,Tetrodotoxin (TTX,河豚毒素,and,saxitoxin,Channel-blocking toxin,Batrachotoxin, veratridine and aconitine,Open t

56、he channels inappropriately,Open at more negative potentials,Open much longer than usual,Putting the Pieces Together,page 89,Threshold,Rising phase,Overshoot,Falling phase,Undershoot,Absolute refractory,period,Figure 4.10 The molecular basis of,the action potential,70,Chapter 4 The Action,Potential,

57、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 POTENTIAL IN REALITY,The Volta

58、ge-Gated Sodium Channel,Voltage-Gated Potassium Channels,Putting the Pieces Together,ACTION POTENTIAL CONDUCTION,Factor influencing conduction velocity,ACTION POTENTIALS, AXONS, AND,Figure 4.11 Action potential,conduction,Figure 4.11,Action potential conduction,The entry of positive charge,during th

59、e 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,Factors 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,Temperature,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 con