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Partof eachtitin moleculeiscloselyassociatedwith a myosinthickfilament(whichswitchespolarityat theM line);the restof the titin moleculeiselasticand changeslengthasthesarcomerecontractsand relaxes.Eachnebulinmoleculeis exactlythe lengthofa thin filament.Theactinfilamentsarealsocoatedwith tropomyosinandtroponin(not shown;seeFigurei6-78)and are cappedat both ends.Tropomodulincapsthe minusend of theactinfilaments,and CapZanchorstheplusend at the Z disc,whichalsocontainso(-actinin.1029THECYTOSKELETONAND CELLBEHAVIORo l a s m am e m b r a n eCa2*-releasec h an n e l stransverse(T)t u b u l e sf o r m e dfrom invaginationso f p l a s m am e m b r a n eics ar c o p l a s mreticulum05pmd e p o l a r i z e dT - t u b u l em e m b r a n eaal.:apolarizedT-tubule tmembraneaa(A)1:iji: ICYTOSOL35nmat.t'i:.:llfarl':rralairil.!!liir.:i't'r..t:,arllili:!lIthis electrical excitation spreadsrapidly into a seriesof membraneous folds, thetransverse tubules, or T tubules, that extend inward from the plasma membranearound each myofibril.
The signal is then relayed across a small gap to tlre sarcoplasmic reticulum, an adjacentweb-like sheath of modified endoplasmic reticulum that surrounds each myofibril like a net stocking (Figure lg-77{and B).rWhen the incoming action potential activates a Ca2+channel in the T-tubulemembrane, a Ca2+influx triggers the opening of Ca2+-releasechannels in thesarcoplasmic reticulum (Figure l6-77C). CaZ*flooding into the cytosol then initiates the contraction of each myofibril.
Becausethe signal from the muscle-cellplasma membrane is passed within milliseconds (via the T tubules and sarcoplasmic reticulum) to every sarcomere in the cell, all of the myofibrils in thecell contract at once. The increasein Ca2*concentration is transient becausetheCa2* is rapidly pumped back into the sarcoplasmic reticulum by an abundant,AlP-dependent Ca2+-pump (also called a Caz*-ATPase)in its membrane (seeFigure 1l-I3). Typically, the cytoplasmic Ca2* concentration is restored to resting levels within 30 msec, allowing the myofibrils to relax. Thus, muscle contraction depends on two processesthat consume enormous amounts ofATP: filament sliding, driven by the ATPase of the myosin motor domain, and Ca2*pumping, driven by the Caz*-pump.The Ca2* dependence of vertebrate skeletal muscle contraction, and henceits dependence on motor commands transmitted via nerves, is due entirely to aset of specialized accessoryproteins that are closely associatedwith the actinthin filaments.
One of these accessoryproteins is a muscle form of tropomyosin,an elongated molecule that binds along the groove of the actin helix. The otheris troponin, a complex of three polypeptides, troponins T I, and C (named fortheir tropomyosin-binding, inhibitory, and Ca2*-binding activities, respectively). Troponin I binds to actin as well as to troponin T. In a resting muscle, thetroponin I-T complex pulls the tropomyosin out of its normal binding grooveinto a position along the actin filament that interferes with the binding ofFigure16-77T tubulesand thesarcoplasmicreticulum.(A)Drawingofthe two membranesystemsthat relaythesignalto contractfrom the musclecellplasmamembraneto all of the myofibrilsin the cell.(B)Electronmicrographshowingtwo T tubules.Notethe positionchannelsin theof the largeCa2+-releasereticulummembrane;theysarcoplasmic"feet"thatlook likesquare-shapedconnectto the adjacentT-tubulediagrammembrane.(C)Schematicchannelinshowinghow a Ca2+-releasereticulummembraneisthe sarcoolasmicthought to be opened by the activationof a voltage-gatedCa2+channel.(8,courtesyof ClaraFranzini-Armstrong.)1030Chapter16:TheCytoskeletont r o p o ni ncomPlexrcmyosin-bindingsite exposedby Ca'*-mediatedtropomyosinmovementtropomvosinT+ ca2*ca2*,".10"tFigure16-78Thecontrolof skeletalmusclecontractionby troponin.(A)A skeletalmusclecellthinfilament,showingthepositionsof tropomyosinandtroponinalongtheactinfilament.Eachtropomyosinmoleculehassevenevenlyspacedregionswithsimilaraminoacidsequences,eachof whichisthoughtto bindto anactinsubunitin thefilament.(B)A thinfilament(bindingshownend-on,illustratinghowCa2+to troponin)isthoughtto relievethetropomyosinblockageof theinteractionbetweenactinandthemyosinhead.(A,adaptedfromG.N.Phillips,J.P.FillersandC.Cohen,J.Mol.Biol.192:111-131,1986.WithpermissionfromAcademicPress.)myosin heads, thereby preventing any force-generating interaction.
\Mhen thelevel of Ca2*is raised, troponin C-which binds up to four molecules of Caz+causes troponin I to release its hold on actin. This allows the tropomyosinmolecules to slip back into their normal position so that the myosin heads canwalk along the actin filaments (Figure f 6-78). Troponin C is closely related tothe ubiquitous Caz*-binding protein calmodulin (see Figure lS=44); it can bethought of as a specialized form of calmodulin that has acquired binding sitesfor troponin I and troponin ! thereby ensuring that the myofibril respondsextremely rapidly to an increase in Ca2+concentration.In smooth muscle cells, so-called because they lack the regular striations ofskeletalmuscle, contraction is also triggered by an influx of calcium ions, but theregulatory mechanism is different. Smooth muscle forms the contractile portionof the stomach, intestine, and uterus, the walls of arteries,and many other structures requiring slow and sustained contractions.
smooth muscle is composed ofsheets of highly elongated spindle-shaped cells, each with a single nucleus.Smooth muscle cells do not expressthe troponins. Instead, Caz* influx into thecell regulates contraction by two mechanisms that depend on the ubiquitouscalcium binding protein calmodulin.First, Ca2+-boundcalmodulin binds to an actin-binding protein, caldesmon,which blocks the actin sites where the myosin motor heads would normallybind. This causesthe caldesmon to fall off of the actin filaments, preparing thefilaments for contraction. Second,smooth muscle myosin is phosphorylated onone of its two light chains by myosin light chain kinase (MLCK.),as describedpreviously for regulation of nonmuscle myosin II (see Figure 16-72).lVhen thelight chain is phosphorylated, the myosin head can interact with actin filamentsand cause contraction; when it is dephosphorylated, the myosin head tends todissociatefrom actin and becomes inactive (in contrast to nonmuscle myosin II,light chain dephosphorylation does not cause thick filament disassembly insmooth muscle cells).
MLCK requires bound ca2*/calmodulin to be fully active.External signaling molecules such as adrenaline (epinephrine) can also regulate the contractile activity of smooth muscle. Adrenaline binding to its G-protein-coupled cell surface receptor causesan increase in the intracellular level ofcyclic AMf; which in turn activates cyclic-AMP-dependent protein kinase (pKA)(seeFigure l5-35). PKA phosphorylates and inactivates MLCK, thereby causingthe smooth muscle cell to relax.The phosphorylation events that regulate contraction in smooth musclecells occur realtively slowly, so that maximum contraction often requires nearlya second (compared with the few milliseconds required for contraction of askeletal muscle cell).
But rapid activation of contraction is not important insmooth muscle: its myosin II hydrolyzes ArP about l0 times more slowly thanskeletal muscle myosin, producing a slow cycle of myosin conformationalchanges that results in slow contraction.THECYTOSKELETONANDCELLBEHAVIOR1031HeartMusclels a PreciselyEngineeredMachine<AGGT>The heart is the most heavilyworked muscle in the body, contracting about 3 billion (3 x 10s)times during the course of a human lifetime. This number is aboutthe same as the average number of revolutions in the lifetime of an automobile'sinternal combustion engine.
Heart cells expressseveralspecific isoforms of cardiac muscle myosin and cardiac muscle actin. Even subtle changesin these contractile proteins expressed in the heart-changes that would not cause anynoticeable consequencesin other tissues-can cause serious heart disease(Figure 16-79).The normal cardiac contractile apparatus is such a highly tuned machinethat a tiny abnormality anywhere in the works can be enough to gradually wearit down over years of repetitive motion. Familial hypertrophic cardiomyopathy isa frequent cause of sudden death in young athletes.
It is a genetically dominantinherited condition that affects about two out of every thousand people, and itis associated with heart enlargement, abnormally small coronary vessels,anddisturbances in heart rhythm (cardiac arrhythmias). The cause of this conditionis either any one of over 40 subtle point mutations in the genesencoding cardiacB myosin heavy chain (almost all causing changesin or near the motor domain),or one of about a dozen mutations in other genes encoding contractile proteins-including myosin light chains, cardiac troponin, and tropomyosin. Minormissensemutations in the cardiac actin gene cause another type of heart condition, called dilated cardiomyopathy, that also frequently results in early heartfailure.Ciliaand FlagellaAreMotileStructuresBuiltfrom Microtubulesa n dD y n e i n sJust as myofibrils are highly specialized and efficient motility machines builtfrom actin and myosin filaments, cilia and flagella are highly specialized andefficient motility structures built from microtubules and dynein.
Both cilia andflagella are hair-like cell appendagesthat have a bundle of microtubules at theircore. Flagella are found on sperm and many protozoa. By their undulatingmotion, they enable the cells to which they are attached to swim through liquidmedia (Figure f 6-80A). Cilia tend to be shorter than flagella and are organizedin a similar fashion, but they beat with a whip-like motion that resembles thebreast stroke in swimming (Figure f6-808). The cycles of adjacent cilia arealmost but not quite in synchrony, creating the wave-like patterns that can beseen in fields of beating cilia under the microscope. Ciliary beating can eitherpropel single cells through a fluid (asin the swimming of the protozoan Paramecium) or can move fluid over the surface of a group of cells in a tissue.
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