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1、P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:4016INTRACELLULAR SIGNALINGThebehaviorofcellsisnotconstant.Cellsneedtobeabletoaltertheirbehaviorinresponseto internal changes or to external events,and the internal signaling mechanisms that allowthem to do so are varied and complex.We will begi
2、n by continuing the story begun inChapter 15 and explain how calcium ions carry a signal from the plasma membrane ofnerve cells to vesicles deep within the cytosol.The rest of the chapter will describe someother very different methods of intracellular signaling.CALCIUMCalcium ions are present at a v
3、ery low concentration(about 100 nmol liter1)in the cytosolofarestingcell.Anenormousnumberofprocessesinmanytypesofcellsareactivatedwhenthe concentration of calcium rises.Calcium can move into the cytosol from two sources:the extracellular medium or the endoplasmic reticulum.Calcium Can Enter from the
4、 Extracellular MediumInChapter15,wesawhowheatingthehandcausesactionpotentialstotravelfromthehandto the spinal cord along the axons of pain receptors.When the action potential reaches theproximal axon terminal,the amino acid glutamate is released onto the surface of anothernerve cell,the pain relay c
5、ell.Glutamate is a transmitter that stimulates the pain relay nervecell,so that the message that the finger is being damaged is passed toward the brain.Cell Biology:A Short Course,Second Edition,by Stephen R.Bolsover,Jeremy S.Hyams,Elizabeth A.Shephard,Hugh A.White,Claudia G.WiedemannISBN 0-471-2639
6、3-1 CopyrightC?2004 by John Wiley&Sons,Inc.341P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40342INTRACELLULAR SIGNALING100 nm gap100 nm gapspinal cordvesicles containing100 m mol liter1glutamatevoltage-gatedcalcium channelsvoltage-gatedsodium channelspotassiumchannelsto skincell body ofpai
7、n receptorpain relay nerve cellproximal axon terminal 70 mVCa2+=100 n molliter1+30 mVCa2+=1 molliter1Ca2+=2 m mol liter1Ca2+=2 m mol liter1exocytosis ofglutamatepainrelaynervecellpainrelaynervecellFigure 16.1.Calcium ions entering the cytosol from the extracellular fluid activate regulatedexocytosis
8、 in the proximal axon terminal of the pain receptor nerve cell.P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40CALCIUM343The proximal axon terminal of the nerve cell is unmyelinated,so that the plasmamembrane is exposed to the extracellular medium(Fig.16.1).The membrane contains notonlypota
9、ssiumchannelsandvoltage-gatedsodiumchannels,butalsovoltage-gatedcalciumchannels.These are closed in a resting cell,but when an action potential travels in fromthe skin and depolarizes the plasma membrane of the proximal axon terminal,the voltage-gated calcium channels open.Calcium ions pour in,incre
10、asing their concentration in thecytosol by 10 times,from the normal concentration of 100 nmol liter1to 1 mol liter1.At the proximal axon terminal the cytosol of the nerve cell contains regulated exocytoticvesicles(page 229).In the case of the pain receptor,these vesicles are filled with sodiumglutam
11、ate.In response to the increased concentration of cytosolic calcium the regulatedexocytotic vesicles move to the plasma membrane and fuse with it,releasing their contentsinto the extracellular medium.The glutamate then diffuses across the gap to the pain relaycell,stimulating it(we will describe how
12、 on page 372).As the action potential in the axonterminal of the pain receptor cell is over in 1 ms,the voltage-gated calcium channels do nothave time to inactivate.They simply return to the ready-to-open state and can be reopenedimmediately by the next action potential that arrives.?Example 16.1Vis
13、ualizing Calcium Signals(a)(b)Calcium signals in cells can be visualized by using dyes that fluoresce brightly when they bindcalcium.The images in the figure show a cell body of a pain receptor cell that has been filled with acalciumindicatordye.Inthefirstimage,atrest,thecellisdim.Thesecondimagewasa
14、cquiredafter100 ms of depolarization.In this the edges of the cell are bright because calcium ions have enteredthroughvoltage-gatedcalciumchannels.Thebrightobjectinthelowerpartofthecellisthenucleus.In the process that we have described,calcium ions act as a link between the depolar-ization of the pl
15、asma membrane and the regulated exocytotic vesicles within the cytosol.P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40344INTRACELLULAR SIGNALINGCalciumionsareintracellularmessengers.Regulatedexocytoticvesiclesthataretriggeredby an increase of cytosolic calcium concentration were first disc
16、overed in nerve cells butare now known to be a feature of almost all cells.Before we continue with the topic of intracellular messengers,we will review twogeneralpointsraisedbyourdescriptionofthepainreceptorproximalaxonterminal.Thefirstpointisthatdifferentnervecellsreleasedifferenttransmitters.Gluta
17、mateisintheexocytoticvesiclesofmanynervecells,butothernervecellsreleaseothertransmitters.Thesecondpointconcerns nomenclature.Many nerve cells,like the pain receptor,have their axon terminalsclose to a second cell and release their transmitter onto it.In such cases the completeunit of axon terminal,g
18、ap,and the part of the second cell that receives the transmitteris called a synapse.The part of the axon terminal that releases transmitter is called apresynaptic terminal,and the cell upon which the transmitter is released is called thepostsynaptic cell.Many nerve cells do not come close enough to
19、a specific second cell toformasynapsebutsimplyreleasetransmitterfromtheiraxonterminalsintotheextracellularmedium.Calcium Can Be Released from the Endoplasmic ReticulumCells may show an increase of cytosolic calcium not because of an action potential butbecause of the appearance of a transmitter or o
20、ther chemical in the extracellular medium.Thepresenceofthechemicalisdetectedbyintegralmembraneproteins,eachoneareceptorthat recognizes a particular chemical with high affinity.These receptors then participate ina more general mechanism,the end result of which is the release of calcium ions from thes
21、mooth endoplasmic reticulum into the cytosol.This mechanism will be illustrated with theparticular example of blood platelets.We will then discuss how much of the mechanism isgeneral to a wider range of cells.Platelets are common in the blood.They are small fragments of cells and contain nonucleus,b
22、ut they do have a plasma membrane and some endoplasmic reticulum.Bloodplatelets use the release of calcium from the endoplasmic reticulum as one step in themechanism of blood clotting(Figs.16.2 and 16.3).Two new mechanisms are involved incalcium release from the endoplasmic reticulum.The inositol tr
23、isphosphate-gated calciumchannel(Fig.16.3),like the voltage-gated calcium channel,allows only calcium ions topass.Most of the time its gate is shut,and no ions flow.It is not opened by a change in thevoltage across the endoplasmic reticulum membrane.Instead,when the intracellular soluteinositol tris
24、phosphate(IP3for short)binds to the cytosolic face of the channel,the channelchanges to an open shape.ThesecondnewmechanismthatwemustdescribeistheonethatmakesIP3(Fig.16.2).If a blood vessel is cut,cytosol from damaged cells at the edge of the cut can leakinto the blood.The appearance of solutes that
25、 normally are found only inside cells is asure sign that damage has occurred.Adenosine diphosphate(ADP)is one such solute,and it acts to stimulate platelets,causing them to begin a blood clot to help plug thedamaged vessel.The plasma membrane of the platelet contains a protein receptor thatbinds ADP
26、,that is,ADP is its ligand.When the ADP has bound,the receptor,which isfree to move in the plasma membrane,becomes a guanine nucleotide exchange factor(page 218)for a trimeric G protein called Gq.Like the GTPases Ran,ARF,and Rabthat we have met earlier,trimeric G proteins are GTPases that activate t
27、arget proteinswhen they have GTP bound,but turn themselves off by hydrolyzing the GTP to GDP.Trimeric G proteins have a slight additional complication in that,as the name indicates,P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40OPOOOOOOPOOOOPOGTPGDPGTPPIP2trimericG proteinGqphospholipaseCA
28、DPreceptorGDPADPDAGOHOPOOOOOOPOOOOPOinositoltrisphosphateblood plateletsADP released from damaged cells in vessel wallFigure 16.2.ADP from damaged cells activates Gqand hence phospholipase C in platelets.345P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40346INTRACELLULAR SIGNALINGCa+endopla
29、smic reticulumblood platelethigh Ca+interior ofendoplasmicreticulumcytosolCa+Ca+IP3 bindsIP3 binding siteADPIP3PIP2DAGFigure16.3.Theinositoltrisphosphate-gatedcalciumchannelreceptorisacalcium-selectivechan-nel in the membrane of the endoplasmic reticulum.An increase of cytosolic calcium concentratio
30、nin platelets makes them sticky,initiating blood clotting.they are composed of three subunits.The subunit is homologous to the GTPases wehave met before,while the and subunits dissociate from the subunit when it hasGTP bound and only reassociate when the GTP has been hydrolyzed.GTP-loaded Gqactivate
31、s the isoform of an enzyme called phosphoinositide phospholipase C,which wewill call phospholipase C or just PLC.(The capital C refers to the bond hydrolyzed bythe enzyme;A,B,and D phospholipases also exist,but we will not meet them in thisbook).PLC specifically hydrolyzes phosphatidylinositol bisph
32、osphate(PIP2for short),a phospholipid in the plasma membrane that has phosphorylated inositol as its polar headgroup.HydrolysisreleasestheIP3todiffusefreelyinthecytosol,leavingbehindtheglycerolbackbone with its attached fatty acids:this residual lipid is called diacylglycerol,or DAG.As it diffuses t
33、hrough the cytosol,IP3reaches the endoplasmic reticulum and binds to theinositol trisphosphate-gated calcium channels.The inositol trisphosphate-gated calciumP1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40Ca+ATPADPactivate force generation by cytoskeletonglycogenglucoseactivate production
34、of glucose ready for use by glycolysis and hence mitochondriaATPGTPcAMPactivate enzymes of Krebs cycle in mitochondriamitochondrial calcium channelporinadenylate cyclasemuscle cellendoplasmic reticulumadrenaline-adrenergic receptorstimulusfromnerveFigure 16.4.Calcium and cyclic-AMP activate distinct
35、 but overlapping sets of target processes in skeletal muscle cells.347P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40348INTRACELLULAR SIGNALINGchannels open,and calcium ions pour out of the endoplasmic reticulum into the cytosol.The increase of calcium concentration causes the platelet to
36、change shape and to becomevery sticky,so platelets begin to clump together in a clot.Phosphatidylinositolbisphosphate,Gq,PLC,andtheinositoltrisphosphate-gatedcal-cium channel are found in almost all eukaryotic cells,but the distribution of the ADPreceptor is more restricted.Only cells that express t
37、he ADP receptor will show an increaseof cytosolic calcium concentration in response to ADP.Other cells respond to other chem-icals.Each produces a receptor specific for that chemical,which then activates Gq.Over100 such receptors are known.We will meet two more in the next chapter.Processes Activate
38、d by Cytosolic Calcium Are Extremely DiverseThe targets activated by an increase of cytosolic calcium concentration differ betweendifferent cells.An increase of calcium is a crude signal that says“do it”but contains noinformation about what the cell should do.This depends on what the cell was design
39、ed todo.Cells and cell regions designed for regulated exocytosis(e.g.,salivary gland cells andaxon terminals)exocytose when cytosolic calcium increases.Cells designed to contract(e.g.,muscle cells)contract when calcium increases,and so on.In each case,the calciumions bind to a calcium-binding protei
40、n;the calcium ioncalcium-binding protein complexactivates the target process.In skeletal muscle cells(page 14)a transmitter released from nerve axon terminalsleads to the escape of calcium from the endoplasmic reticulum(Fig.16.4).This activatesseveral processes.First,calcium ions bind to a protein c
41、alled troponin that is attached to thecytoskeleton.This causes the cytoskeleton to contract,using the energy released by ATPhydrolysis to do mechanical work(page 393).Second,the calcium binds to the proteincalmodulin,which in turn activates glycogen phosphorylase kinase and hence glycogenbreakdown a
42、s part of the feedforward control of energy metabolism(page 305).Mitochondria are also affected by calcium,which passes down its electrochemicalgradient from the cytosol into the mitochondrial matrix through a calcium channel.Oncethere,calcium stimulates the mitochondria to increase the production o
43、f NADH and ATP(page 305).fIN DEPTH 16.1 Ryanodine ReceptorsMany cells contain a second type of calcium channel in the membrane of the endo-plasmic reticulum.This channel was initially distinguished from the IP3receptor bythe fact that it bound the plant alkaloid ryanodine,so it was called the ryanod
44、inereceptor.Ryanodine receptors were first identified in skeletal muscle.In these cellsthey are physically linked to voltage-gated calcium channels in the plasma mem-brane(left-handsideofdiagram).Whenthevoltage-gatedcalciumchannelsswitchto their open configuration,they induce the ryanodine receptors
45、 below them toswitch into an open configuration,allowing calcium to flow out of the smoothendoplasmic reticulum into the cytosol.No such direct linkage between ryanodine receptors and plasma membranechannels is found in other cell types.Instead,ryanodine receptors are openedwhen the concentration of
46、 calcium ions in the cytosol rises above a critical level.For example,in heart muscle(right-hand side of diagram)depolarization causesvoltage-gated calcium channels in the plasma membrane to open.The calcium ionsthatenterthroughthischannelbindtothecytosolicaspectoftheryanodinerecep-tor,causingittoop
47、entoo,allowingcalciumtoflowoutofthesmoothendoplasmicreticulum into the cytosol.P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40Ca+Ca+depolarizationrepolarizationdepolarizationrepolarizationlumen ofendoplasmicreticulumlumen ofendoplasmicreticulumryanodinereceptorcalciumbindingsiteryanodinere
48、ceptormembrane ofendoplasmicreticulumplasmalemmaextracellular mediumcardiac musclevoltage gated calcium channelvoltage gated calcium channelskeletal muscle cellCa+349P1:IOIWY001-16WY001-Bolsover-v2.clsSeptember 15,200319:40350INTRACELLULAR SIGNALINGThe same simple intracellular messenger,calcium,has
49、 many different actions insidethe skeletal muscle cell.Under its influence the cytoskeleton begins to use ATP,glycogenphosphorylasereleasesmoreglucose,andthemitochondriaproducemoreATP.Theskeletalmuscle cell is an example of how diverse mechanisms inside a cell can be integrated by theaction of intra
50、cellular messengers.?Example 16.2Training for Anaerobic RespirationMuscle cells that are contracted for long periods,cutting off the blood supplysuch as those inthe arms of rock climbershave a much enhanced capacity for anaerobic respiration compared tothose that are used briefly and then relaxed(su