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1、P1:IOIWY001-15WY001-Bolsover-v2.clsAugust 21,200319:3615THE ACTION POTENTIALAn action potential is an explosive change in the voltage across the plasma membrane.Themost sophisticated electrically excitable cellscells that can produce action potentialsare the nerve cells that allow our brains to carr
2、y out the complex electrical data processingcalled thought.However,we will begin with a much simpler electrically excitable cell:thesea urchin egg.THE CALCIUM ACTION POTENTIAL IN SEA URCHIN EGGSInmostanimals,eggsthatarefertilizedbymorethanonespermfailtodevelop.Anumberofmechanisms exist to prevent su
3、ch“polyspermy,”one of which is based on action potentials.Effect of Egg Transmembrane Voltage on Sperm FusionAn experiment first carried out in 1976 by Laurinda Jaffe is illustrated in Figure 15.1a.She impaled a sea urchin egg with a micropipette(page 320).Instead of just measuringthe natural restin
4、g transmembrane voltage(around 70 mV),she depolarized the plasmamembrane by passing positive current through the pipette.We use the word depolarizationto mean any positive shift in the transmembrane voltage,whatever its size or cause.In thiscase an electronic feedback circuit was used to alter the v
5、alue of the current passed thoughthe electrode so that the transmembrane voltage was depolarized to+10 mV and held atCell Biology:A Short Course,Second Edition,by Stephen R.Bolsover,Jeremy S.Hyams,Elizabeth A.Shephard,Hugh A.White,Claudia G.WiedemannISBN 0-471-26393-1 CopyrightC?2004 by John Wiley&S
6、ons,Inc.325P1:IOIWY001-15WY001-Bolsover-v2.clsAugust 21,200319:36326THE ACTION POTENTIALpass whateverelectrical current isnecessary to keep thetransmembranevoltage at+10 mVno sperm fusepass whateverelectrical current isnecessary to keepthe transmembranevoltage at 70 mVmany sperm fuse-celldivision is
7、 abnormaland zygote cannotdevelopsubsequentsperm cannotfuse-celldivision isnormalandzygote willdevelop(a)(b)recordtransmembranevoltage but donot alter itfirst spermsucessfullyfusestransmembranevoltage(mV)70010200 ms100(c)Figure 15.1.In sea urchin eggs transmembrane voltage controls sperm fusion.that
8、 value.This technique,in which the experimenter,not the cell,determines the value ofthe transmembrane voltage,is called voltage clamp.Jaffeobservedthatspermwouldnotfusewitheggsinwhichthetransmembranevoltagewas clamped at+10 mV,and the eggs remained unfertilized(Fig.15.1a).However,an eggclamped at 70
9、 mV(Fig.15.1b)was fertilized by multiple sperm,leading to a defectiveembryo.The transmembrane voltage is able to control the fusion of sperm and egg.When no current is passed through the micropipette,the transmembrane voltage isset by the channels in the egg plasma membrane(Fig.15.1c).The resting vo
10、ltage of theunfertilized egg is set by potassium movement through potassium channels.The first spermthat arrives can fuse because the transmembrane voltage is 70 mV.But within 100 ms,the transmembrane voltage depolarizes to+10 mV and further sperm fusion is blocked.Thus transmembrane voltage changes
11、 to prevent multiple sperm fusion.The sea urchinP1:IOIWY001-15WY001-Bolsover-v2.clsAugust 21,200319:36THE CALCIUM ACTION POTENTIAL IN SEA URCHIN EGGS327egg,which when unfertilized has a transmembrane voltage of 70 mV and is receptiveto fertilization,depolarizes its membrane following successful fert
12、ilization to protect itselffrom subsequent fertilization.The result is shown on the right of Figure 15.1c.Only onesperm has fused,so the fertilized egg has the correct number of chromosomes and can goon to develop into an embryo and then into a mature sea urchin.The Voltage-Gated Calcium ChannelTher
13、apiddepolarizationthatoccursuponfertilizationoftheseaurchineggisanexampleofanactionpotential.Likemanycells,urchineggscangenerateactionpotentialsbecausetheirplasma membranes contain,together with potassium channels,an ion-conducting channelcalled the voltage-gated calcium channel.Figure15.2showshowth
14、evoltage-gatedcalciumchannelworks.Ontheleftistheshapeof the protein when the transmembrane voltage is 70 mV,as in an unfertilized egg.Theprotein forms a tube,but it is not open all the way through the membrane.If the membranedepolarizes so that the cytosol is less negative or even becomes positive,p
15、ositively chargedaminoacidresiduesontheproteinarerepelled,poppingthetubeintoanopenstate.Calciumions can now pass through the channel.If the membrane is then repolarized,the channelquickly recloses because the positive charges are pulled back toward the inside of the cell.A proteindomain in the cytos
16、ol called the inactivation plug is constantly jiggling aboutat the end of a flexible link and can bind to the inside of the open channel.The resultingblockage is called inactivation,and it occurs after about 100 ms.As long as the plasmamembrane remains depolarized,the voltage-gated calcium channel w
17、ill remain inactivated.When the plasma membrane is repolarized,the positive charges are attracted back towardthe inside of the cell,squeezing the plug out.In summary:1.When the transmembrane voltage is 70 mV,the voltage-gated calcium channel isgated shut.2.When the plasma membrane is depolarized,the
18、 channel opens rapidly and afterabout 100 ms inactivates.repolarizationextracellular mediumCytosolCa+spontaneous after 100 msdepolarizationinactivation plugrepolarizationFigure 15.2.The voltage-gated calcium channel.P1:IOIWY001-15WY001-Bolsover-v2.clsAugust 21,200319:36328THE ACTION POTENTIAL3.After
19、 the channel has gone through this cycle,it must spend at least 100 ms with thetransmembrane voltage at the resting voltage before it can be opened by a seconddepolarization.The voltage-gated calcium channel goes through this process whether or not calcium ionsare present.To understand the action po
20、tential,we must now think about the effect thatmovements of calcium ions through this channel have on the transmembrane voltage.The Calcium Action PotentialAt point A in Figure 15.3 the egg is unfertilized.The potassium channels are open andset the transmembrane voltage to 70 mV.This negative voltag
21、e closes the voltage-gatedcalcium channels.At point B we show what happens if an experimenter passes enough current down amicropipettetodepolarizetheplasmamembraneby10mV,to60mV,andthenstopspass-ing current and once again allows the ion channels in the plasma membrane to determinethe transmembrane vo
22、ltage.This small depolarization opens only a very few voltage-gatedcalcium channels,so what happens next depends almost entirely on the movement of ionsthrough the potassium channels.The slight decrease in the negative voltage of the cytosolreduces its attraction to potassium ions,and they move out
23、of the cell down their concen-tration gradient.In so doing,they carry positive charge away from the cytosol,and thetransmembrane voltage returns to its resting value of 70 mV.At point C,the experiment is repeated,but this time the membrane is fleetingly depo-larized by 20 to 50 mV.Again,most of the
24、voltage-gated calcium channels stay shut,butsome open,and calcium ions rush into the cell down their electrochemical gradient.Theflow of positive charge inward on the calcium ions outweighs the outward flow of positivechargeonpotassiumions,sothecytosolisgainingpositivechargeanditsvoltageismovingin t
25、he positive direction.As a result more voltage-gated calcium channels open,and thisallows more calcium ions to flood in.This is an example of positive feedback(page 303)because every calcium ion that moves in makes the cytosol more positive,causing morecalcium channels to open,and therefore making i
26、t easier for the next calcium ion to movein.AtpointD,allthecalciumchannelsareopen,theinwardcalciumcurrentismuchgreaterthan the outward potassium current,and the plasma membrane is rapidly depolarizing.However,after 100 ms,the voltage-gated calcium channels begin to inactivate and theinward flow of c
27、alcium ions stops.The plasma membrane stops depolarizing and returns to70 mV as potassium leaves through its channels.This experiment shows the critical feature of an action potential:it is all or nothing.The depolarization at point B was too small to generate an action potential,and the trans-membr
28、anevoltagesimplyfellbacktoitsrestingstate.AtpointCthedepolarizationwasbigenoughtostarttheprocess,andtheactionpotentialtookoffinanexplosive,self-amplifyingway until all the voltage-gated calcium channels were open and the plasma membrane hadgreatly depolarized.In all excitable cells there is a thresh
29、old for initiating an action poten-tial;in the sea urchin egg it lies between 60 and 50 mV.Depolarizations to below thethreshold elicit nothing;depolarizations to voltages more positive than the threshold elicitthecompleteactionpotential.Attheheartoftheactionpotentialisapositivefeedbackloop.Depolari
30、zation causes voltage-gated calcium channels to open,and open calcium channelscause depolarization.P1:IOIWY001-15WY001-Bolsover-v2.clsAugust 21,200319:36THE CALCIUM ACTION POTENTIAL IN SEA URCHIN EGGS329BACDE1050703010transmembrane voltageDK+K+Ca2+Ca2+Ca2+Ca2+Ca2+BK+K+1 stimeEK+K+Ca2+membrane of spe
31、rmCK+K+Ca2+voltage-gated calcium channelsApotassium channels70 mV60 mV50 mV30 mV50 mVFigure 15.3.The calcium action potential in a sea urchin egg.In nature the initial depolarization that sets off an action potential is produced by thesperm.This is illustrated at point E.The membrane of the sperm co
32、ntains an unusual typeof calcium channel that is open even at the resting voltage.When the membrane of thesperm is added to that of the egg,the inward current through the sperms calcium channelsdepolarizes the plasma membrane of the egg by 20 mV to 50 mV,enough to cause theP1:IOIWY001-15WY001-Bolsov
33、er-v2.clsAugust 21,200319:36330THE ACTION POTENTIALcritical number of the eggs own voltage-gated calcium channels to open.The mechanismof the action potential takes over and the plasma membrane depolarizes rapidly to+10 mV.Thegraphhasbeencutoffattheright-handedge(wherethevoltage-gatedcalciumchannels
34、inactivate)where other mechanisms,not described here,take over and maintain a positivetransmembrane voltage.The action potential has served its purpose in preventing secondand subsequent sperm fusions in the 100 ms following the first fertilization.THE VOLTAGE-GATED SODIUM CHANNEL IN NERVE CELLSThev
35、oltage-gatedcalciumchannelappearedearlyinevolutionandisfoundinalleukaryotesandinawidevarietyofcelltypes.Lateroninevolution,whenmulticellularorganismsarose,there was a need for a system that could send electrical signals rapidly over long distanceswithin the body.This system uses sodium rather than c
36、alcium ions.The Voltage-Gated Sodium ChannelThe cells in multicellular animals that are specialized for rapid conduction have a second,voltage-gated channel that is selective for sodium instead of calcium ions.It operates likethe voltage-gated calcium channel,but both opening and inactivation are fa
37、ster(Fig.15.4).In summary:1.When the transmembrane voltage is 70 mV,the voltage-gated sodium channel isgated shut.2.When the plasma membrane is depolarized,the channel opens rapidly and then,after about 1 ms,inactivates.3.After the channel has gone through this cycle,it must spend at least 1 ms with
38、 thetransmembrane voltage at the resting voltage before it can be opened by a seconddepolarization.repolarizationextracellular mediumCytosolNa+spontaneous after 1 msdepolarizationinactivation plugrepolarizationFigure 15.4.The voltage-gated sodium channel.P1:IOIWY001-15WY001-Bolsover-v2.clsAugust 21,
39、200319:36THE VOLTAGE-GATED SODIUM CHANNEL IN NERVE CELLS331?Example 15.1Chewing off the Inactivation PlugProteases are enzymes that hydrolyze the peptide bonds within proteins.In 1976 Emilio Rojas andBernardo Rudy investigated the effect of introducing protease into squid axons.The membrane ofsquid
40、axons contains voltage-gated sodium channels that,like ours,normally inactivate about 1 msafter they are opened by a depolarization.However,after introduction of the protease,depolariza-tion caused the voltage-gated sodium channels to open and remain open indefinitely,although thechannels would clos
41、e if the membrane was repolarized.Back in 1976 Rojas and Rudy had no ideawhy this should be so.Now we can understand the resultthe protease cuts the linker between themain part of the voltage-gated sodium channel and the inactivation plug.The plug then floats offand is not available to block the ope
42、n channel.depolarizationrepolarizationNa+Likecalcium,sodiumisatamuchhigherconcentrationoutsidethecellthaninside.Inamammal,the sodium concentration in the blood is 150 mmol liter1,whereas in the cytosolit is 10 mmol liter1.When voltage-gated sodium channels open,sodium ions rush into thecell carrying
43、 positive charge and depolarizing the plasma membrane.This then favors theopeningofmorevoltage-gatedsodiumchannels,andsoon.Thispositivefeedbackproducesa depolarization to+30 mV called the sodium action potential.Because the voltage-gatedsodiumchannelsinactivatesoquickly,thesodium-basedactionpotentia
44、llastsonlyfor1ms.?MedicalRelevance15.1A Sodium“Channelopathy”Epilepsy,in which nerve cells in the brain fire action potentials in an uncontrolledfashion,isnotuncommoninyoungchildrenbutoftenclearsupasthechildgetsolder.However,one form of childhood-onset epilepsy,termed GEFS+for“generalized epilepsy w
45、ithfebrile seizures that extend beyond six years of age,”does not improve with age.Robyn Wallaceand co-workers in Australia showed that this condition could be caused by a mutation that slowsthe rate at which the inactivation plug moves to block the voltage-gated sodium channel.The slowrate of inact
46、ivation makes it easier for stimuli to trigger action potentials in the nerve cells in thebrain.Although enough sodium ions move into the cell to dramatically change the trans-membrane voltage,the concentration of sodium ions inside the cell is increased only veryslightly.Theamountdependsontheelectr
47、icalcapacitanceofthecellmembraneandthecellvolume,but,for example,it can be calculated that a single sodium-based action potentialincreases the sodium concentration in the nerve cell axon of Figure 15.7 by only 250 nmolliter1.P1:IOIWY001-15WY001-Bolsover-v2.clsAugust 21,200319:36332THE ACTION POTENTI
48、ALElectrical Transmission down a Nerve Cell AxonFigures 15.5 and 15.6 show how one nerve cell,a pain receptor,uses sodium-based actionpotentials to signal to the central nervous system.The cell body is close to the spinal cordandextendsanaxonthatbranchestothespinalcordandouttothebody.Theparticularpa
49、inreceptor illustrated in Figure 15.5 sends its axon for almost a meter to the tip of a finger,an extraordinary distance for a single cell.Potentially damaging events are detected at thefinger,and the message is passed on to another nerve cell(a pain relay cell)in the spinalcord.We will now explain
50、how this function is performed.Figure 15.5 shows the transmembrane voltage of the pain receptor at the two axonterminals,one near the tip of the finger(green line)and one at the opposite end of thehand inwarm airspinal cordpain relay nerve cellproximal axon terminalrepresentstransmembrane voltagemea