3Classification of the Muscle According to the structure: Striated Muscle, Smooth MuscleAccording to the nerve innervation: Voluntary Muscle, Involuntary MuscleAccording to the Function: Skeletal Muscle, Cardiac Contraction, Smooth Muscle
8New Ion Channel Players Voltage-gated Ca2+ channelin presynaptic nerve terminalmediates neurotransmitter releaseNicotinic Acetylcholine Receptor Channelin muscle neuromuscular junction (postsynaptic membrane, or end plate)mediates electrical transmission from nerve to muscle
9Nerve Terminal Ca2+ channels Structurally similar to Na+ channelsFunctionally similar to Na+ channels exceptactivation occurs at more positive potentialsactivation and inactivation much slower than Na+ channels
11Neuromuscular Transmission: Step by Step - - Nerve action Depolarizationof terminalopens Ca channelsNerve actionpotential invadesaxon terminal-++-+ +Lookhere
12postsynaptic membrane ACh is released and diffuses across Binding of ACh openschannel pore that ispermeable to Na+ and K+.ACh binds to itsreceptor on thepostsynaptic membraneACh is released anddiffuses acrosssynaptic cleft.Ca2+ induces fusion ofvesicles with nerveterminal membrane.AChAChAChNerveterminalCa2+Ca2+Na+Na+Na+Na+K+Na+K+Na+K+K+AChNa+Na+Na+K+OutsideMuscle membraneNa+Na+InsideK+K+Na+K+K+K+K+K+Na+K+Na+
13End Plate Potential (EPP) The movement of Na+ and K+depolarizes muscle membranepotential (EPP)VNaEPPMuscle MembraneVoltage (mV)ThresholdPresynapticterminal-90 mVVKTime (msec)PresynapticAPOutsideMuscle membraneInsideVoltage-gatedNa ChannelsACh Receptor ChannelsInward RectifierK Channels
14Meanwhile ... ACh ACh ACh Choline resynthesized ACh is hydrolyzed by into ACh and repackagedinto vesicleCholine is taken upinto nerve terminalACh is hydrolyzed byAChE into Cholineand acetateACh unbinds fromits receptorso the channel closesNerveterminalCholineAChAcetateAChOutsideMuscle membraneInside
16Neuromuscular Transmission Properties of neuromuscular junction1:1 transmission: A chemical transmission which is designed to assure that every presynaptic action potential results in a postsynaptic oneAn unidirectional processHas a time delay. 20nm/0.5-1msIs easily affect by drugs and some factorsThe NMJ is a site of considerable clinical importance
17Clinical Chemistry Related compounds are Ach is the natural useful in the neuroscienceresearchSuberyldicholine is asynthetic neuromuscularagonist.Ach is the naturalagonist at theneuromuscularjunction.Carbachol and relatedcompounds are usedclinically for GI disorders,glaucoma, salivarygland malfunction, etc.Tubocurarine and other,related compoundsare used to paralyzemuscles during surgery.Tubocurarine competeswith ACh for bindingto receptor- but doesnot open the pore.So tubocurarine is aneuromuscularblocking agent.Carbachol is asynthetic agonistnot hydrolyzed byacetylcholinesterase.Tubocurarine is theprimary paralyticingredient in curare.
18Anticholinesterase Agents Anticholinesterase (anti-ChE) agents inhibit acetylcholinesterase （乙酰胆碱酯酶）prolong excitation at the NMJ
19Anticholinesterase Agents 1. Normal:ACh Choline + AcetateAChE2. With anti - AchE:ACh Choline + Acetateanti - AChE
20Uses of anti-ChE agents Clinical applications (Neostigmine, 新斯的明, Physostigmine毒扁豆碱)Insecticides (organophosphate 有机磷酸酯)Nerve gas (e.g. Sarin 沙林，甲氟膦酸异丙酯。一种用作神经性毒气的化学剂))
21Sarin and Aum Shinrikyo(奥姆真理教) Aum Shinrikyo(奥姆真理教) is a Japanese religious cult obsessed with the apocalypse （启示，天启）.The previously obscure group became infamous in 1995 when some of its members released deadly sarin nerve gas into the Tokyo subway system,killing 12 people and sending more than 5,000 others to hospitals.
22Sarin Sarin, which comes in both liquid and gas forms, is a highly toxic and volatile nerve agent developed by Nazi scientists in Germany in the 1930s.Chemical weapons experts say that sarin gas is 500 times more toxic than cyanide （氢化物） gas.
23NMJ Diseases Myasthenia Gravis （重症肌无力） Autoimmunity to ACh receptorFewer functional ACh receptorsLow “safety factor” for NM transmissionLambert-Eaton syndrome（兰伯特-伊顿综合征 ，癌性肌无力综合征 ）Autoimmunity directed against Ca2＋ channelsReduced ACh release
25Skeletal Muscle Human body contains over 400 skeletal muscles 40-50% of total body weightFunctions of skeletal muscleForce production for locomotion and breathingForce production for postural supportHeat production during cold stress
26Fascicles: bundles, CT(connective tissue) covering on each one Muscle fibers: muscle cells
30SarcomeresSarcomere 肌小节: bundle of alternating thick and thin filamentsSarcomeres join end to end to form myofibrilsThousands per fiber, depending on length of muscleAlternating thick and thin filaments create appearance of striations
32Myosin 肌球蛋白 Myosin head is hinged Bends and straightens during contraction
33Thick filaments (myosin) Bundle of myosin proteins shaped like double-headed golf clubsMyosin heads have two binding sitesActin binding site forms cross bridgeNucleotide binding site binds ATP (Myosin ATPase)Hydrolysis of ATP provides energy to generate power stroke
35Thin filaments (actin) Backbone: two strands of polymerized globular actin – fibrous actinEach actin has myosin binding siteTroponinBinds Ca2+; regulates muscle contractionTropomyosinLies in groove of actin helixBlocks myosin bindingsites in absence of Ca2+
451. Myosin heads form cross bridges Myosin head is tightly bound to actin in rigor stateNothing bound to nucleotide binding site
462. ATP binds to myosinMyosin changes conformation, releases actin
473. ATP hydrolysis ATP is broken down into: ADP + Pi (inorganic phosphate)Both ADP and Pi remain bound to myosin
484. Myosin head changes conformation Myosin head rotates and binds to new actin moleculeMyosin is in high energy configuration
495. Power strokeRelease of Pi from myosin releases head from high energy stateHead pushes on actin filament and causes slidingMyosin head splits ATP and bends toward H zone. This is Power stroke.
506. Release of ADPMyosin head is again tightly bound to actin in rigor stateReady to repeat cycle
51THE CROSS-BRIDGE CYCLE Relaxed state Crossbridge energisedCrossbridge attachmentA + M l ADP l PiCa2+ presentA – M l ATPAlMlADPlPiCrossbridge detachmentTension developsADP + PiATPAlMA, Actin; M, Myosin
53Rigor mortisMyosin cannot release actin until a new ATP molecule bindsRun out of ATP at death, cross-bridges never release
54Need steady supply of ATP! Many contractile cycles occur asynchronously during a single muscle contractionNeed steady supply of ATP!
55Regulation of Contraction Tropomyosin blocks myosin binding in absence of Ca2+Low intracellular Ca2+ when muscle is relaxed
56Ca+2 binds to troponin during contraction Troponin-Ca+2 pulls tropomyosin, unblocking myosin-binding sitesMyosin-actin cross-bridge cycle can now occur
57How does Ca2+ get into cell? Action potential releases intracellular Ca2+ from sarcoplasmic reticulum (SR)SR is modified endoplasmic reticulumMembrane contains Ca2+ pumps to actively transport Ca2+ into SRMaintains high Ca2+ in SR, low Ca2+ in cytoplasm
58The action potential triggers contraction How does the AP trigger contraction?This question has the beginning (AP) and the end (contraction) but it misses lots of things in the middle!We should ask:how does the AP cause release of Ca from the SR, so leading to an increase in [Ca]i?how does an increase in [Ca]i cause contraction?
59Structures involved in EC coupling A band(myosin)I band(actin)Z discContractile proteins in striated muscle are organised into sarcomeresT-tubules and sarcoplasmic reticulum are organised so that Ca release is directed toward the regulatory (Ca binding) proteinsThe association of a t-tubule with SR on either side is often called a ‘triad’ （三联管）(tri meaning three)Z discM lineZ discsarcoplasmicreticulumt-tubulesTriadjunctional feet
61Ca2+ Controls Contraction Ca2+ Channels and PumpsRelease of Ca2+ from the SR triggers contractionReuptake of Ca2+ into SR relaxes muscleSo how is calcium released in response to nerve impulses?Answer has come from studies of antagonist molecules that block Ca2+ channel activity19
63Dihydropyridine Receptor In t-tubules of heart and skeletal muscleNifedipine and other DHP-like molecules bind to the "DHP receptor" in t-tubulesIn heart, DHP receptor is a voltage-gated Ca2+ channelIn skeletal muscle, DHP receptor is apparently a voltage-sensing protein and probably undergoes voltage-dependent conformational changes20
64The "foot structure" in terminal cisternae of SR Ryanodine ReceptorThe "foot structure" in terminal cisternae of SRFoot structure is a Ca2+ channel of unusual designConformation change or Ca2+ -channel activity of DHP receptor apparently gates the ryanodine receptor, opening and closing Ca2+ channelsMany details are yet to be elucidated!21
65Skeletal muscle The AP: moves down the t-tubule voltage change detected by DHP （双氢吡啶） receptorsDHP receptor is essentially a voltage-gated Ca channelis communicated to the ryanodine receptor which opens to allow Ca out of SRactivates contractionoutinvoltage sensor(DHP receptor)junctional foot(ryanodine receptor)sarcoplasmicreticulumsarcolemmaT-tubule
66Cardiac muscle The AP: moves down the t-tubule voltage change detected by DHP receptors (Ca channels) which opens to allow small amount of (trigger) Ca into the fibreCa binds to ryanodine receptors which open to release a large amount of (activator) Ca (CACR)Thus, calcium, not voltage, appears to trigger Ca release in Cardiac muscle!outinvoltage sensor& Ca channel(DHP receptor)junctional foot(ryanodine receptor)sarcoplasmicreticulumsarcolemmaT-tubule
67The Answers! Skeletal Cardiac The trigger for SR release appears to be calcium (Calcium Activated Calcium Release - CACR)The t-tubule membrane has a Ca2+ channel (DHP receptor)The ryanodine receptor is the SR Ca release channelThe ryanodine receptor is Ca-gated & Ca release is proportional to Ca2+ entrySkeletalThe trigger for SR release appears to be voltage (Voltage Activated Calcium Release- VACR)The t-tubule membrane has a voltage sensor (DHP receptor)The ryanodine receptor is the SR Ca release channelCa2+ release is proportional to membrane voltage
68Transverse tubules connect plasma membrane of muscle cell to SR
69Ca2+ release during Excitation-Contraction coupling Action potential on motor endplate travels down T tubulesRyanodyne RCa-release ch.
70Voltage -gated Ca2+ channels open, Ca2+ flows out SR into cytoplasm Ca2+ channels close when action potential ends. Active transport pumps continually return Ca2+ to SRCa ATPase(SERCA)
71Excitation-Contraction Coupling Depolarization of motor end plate (excitation) is coupled to muscular contractionNerve impulse travels along sarcolemma and down T-tubules to cause a release of Ca2+ from SRCa2+ binds to troponin and causes position change in tropomyosin, exposing active sites on actinPermits strong binding state between actin and myosin and contraction occursATP is hydrolyzed and energy goes to myosin head which releases from actin
73IV Factors that Affect the Efficiency of Muscle Contraction
74Tension and LoadThe force exerted on an object by a contracting muscle is known as tension.The force exerted on the muscle by an object (usually its weight) is termed load.According to the time of effect exerted by the loads on the muscle contraction the load was divided into two forms, preload and afterload.
75Preload Preload is a load on the muscle before muscle contraction. Determines the initial length of the muscle before contraction.Initial length is the length of the muscle fiber before its contraction.It is positively proportional to the preload.
76The Effect of Sarcomere Length on Tension The Length – Tension CurveConcept of optimal length
77Types of Contractions I Twitch: a brief mechanical contraction of a single fiber produced by a single action potential at low frequency stimulation is known as single twitch.Tetanus: It means a summation of twitches that occurs at high frequency stimulation
80AfterloadAfterload is a load on the muscle after the beginning of muscle contraction.The reverse force that oppose the contractile force caused by muscle contraction.The afterload does not change the initial length of the muscle,But it can prevent muscle from shortening because a part of force developed by contraction is used to overcome the afterload.
81Types of Contractions (II) Afterload on muscle is resistanceIsometricLength of muscle remains constant. Peak tension produced. Does not involve movementIsotonicLength of muscle changes. Tension fairly constant. Involves movement at jointsResistance and speed of contraction inversely related