Cell PhysiologyCell PhysiologyNeuromuscular and Synaptic Transmission, Neuromuscular and Synaptic Transmission,

Skeletal Muscle, Smooth MuscleSkeletal Muscle, Smooth MuscleLectured by Bien Eli Nillos, MDLectured by Bien Eli Nillos, MD

Neuromuscular and Synaptic Neuromuscular and Synaptic TransmissionTransmission

An action potential in the presynaptic cell An action potential in the presynaptic cell causes depolarization of the presynaptic causes depolarization of the presynaptic terminalterminal

As a result of the depolarization, Calcium As a result of the depolarization, Calcium enters the presynaptic terminal causing enters the presynaptic terminal causing release of neurotransmitter into the release of neurotransmitter into the synaptic cleftsynaptic cleft

SYNAPSE Presynaptic cell

Postsynaptic cell

Synaptic cleft

Neurotransmitter diffuses across the Neurotransmitter diffuses across the synaptic cleft and combines with receptors synaptic cleft and combines with receptors on the postsynaptic cell membraneon the postsynaptic cell membrane

Cause change in its permeability to ions Cause change in its permeability to ions and a change in its membrane potentialand a change in its membrane potential

SYNAPSE Presynaptic cell

Postsynaptic cell

Neuromuscular JunctionNeuromuscular Junction

Synapse between axons of motor neurons Synapse between axons of motor neurons and skeletal muscleand skeletal muscle

Acetylcholine – neurotransmitter released Acetylcholine – neurotransmitter released from the presynaptic terminalfrom the presynaptic terminal

Nicotinic receptor – found at the Nicotinic receptor – found at the postsynaptic terminal, specific for Achpostsynaptic terminal, specific for Ach

Choline acetyltransferase – catalyzes the Choline acetyltransferase – catalyzes the formation of Ach from acetyl coenzyme A formation of Ach from acetyl coenzyme A and choline in the presynaptic terminal. and choline in the presynaptic terminal.

Depolarization of the presynaptic terminal Depolarization of the presynaptic terminal opens Calcium channels.opens Calcium channels.

Calcium uptake causes release of Ach into Calcium uptake causes release of Ach into the synaptic cleft.the synaptic cleft.

The nicotinic Ach receptor is also a Na+ The nicotinic Ach receptor is also a Na+ and K+ ion channel (e.g. ligand-gated and K+ ion channel (e.g. ligand-gated channel)channel)

Because the channels opened by Ach Because the channels opened by Ach conduct both Na and K ions, the conduct both Na and K ions, the postsynaptic membrane potential is postsynaptic membrane potential is depolarized.depolarized.

SYNAPSE Presynaptic cell

Postsynaptic cell

CaCa

+-

++--

Once the end plate is depolarized, local Once the end plate is depolarized, local currents cause depolarization and action currents cause depolarization and action potentials in the adjacent muscle tissue.potentials in the adjacent muscle tissue.

Action potentials in the muscle are Action potentials in the muscle are followed by contraction.followed by contraction.

Ach is degraded to acetyl-CoA and choline Ach is degraded to acetyl-CoA and choline by by acetylcholinesteraseacetylcholinesterase on the muscle on the muscle end plate.end plate.

SYNAPSE Presynaptic cell

Postsynaptic cell

CaCa

+-

++--

+ + +

- - - -

Myasthenia gravis – caused by antibodies Myasthenia gravis – caused by antibodies to the ACh receptorsto the ACh receptors

Characterized by skeletal muscle Characterized by skeletal muscle weakness and fatigability resulting from a weakness and fatigability resulting from a reduced number of ACh receptors on the reduced number of ACh receptors on the muscle end plate.muscle end plate.

Treatment with AChE inhibitors prevents Treatment with AChE inhibitors prevents the degradation of ACh and prolongs the the degradation of ACh and prolongs the action of ACh at the muscle end plate.action of ACh at the muscle end plate.

Summation at SynapsesSummation at Synapses

Spatial summation – occurs when two Spatial summation – occurs when two excitatory inputs arrive at a postsynaptic excitatory inputs arrive at a postsynaptic neuron simultaneously. They produce neuron simultaneously. They produce greater depolarization.greater depolarization.

Temporal summation – occurs when two Temporal summation – occurs when two excitatory inputs arrive at a postsynpatic excitatory inputs arrive at a postsynpatic neurons in rapid succession; they add in neurons in rapid succession; they add in stepwise fashion.stepwise fashion.

NeurotransmittersNeurotransmitters

NorepinephrineNorepinephrine EpinephrineEpinephrine DopamineDopamine SerotoninSerotonin HistamineHistamine GlutamateGlutamate GABAGABA GlycineGlycine

The Skeletal MuscleThe Skeletal Muscle

Skeletal muscles are composed of masses Skeletal muscles are composed of masses of fibers, each an individual cell. of fibers, each an individual cell.

Muscles are composed of muscle fibers; Muscles are composed of muscle fibers; fibers are composed (in part) of myofibrils; fibers are composed (in part) of myofibrils; and myofibrils are composed of and myofibrils are composed of myofilaments.myofilaments.

Each muscle fiber contains about 1000 Each muscle fiber contains about 1000 myofibrils that are 1 m in diameter and run myofibrils that are 1 m in diameter and run the length of the fiber.the length of the fiber.

Myofibrils have no membrane, being Myofibrils have no membrane, being simply surrounded with cytoplasm.simply surrounded with cytoplasm.

The cross-striations of the myofibrils are The cross-striations of the myofibrils are serially repeating units called serially repeating units called sarcomeressarcomeres

A sarcomere is bounded on each end by a A sarcomere is bounded on each end by a disc, called the disc, called the Z disc or Z lineZ disc or Z line. .

Each sarcomere contains an anisotropic Each sarcomere contains an anisotropic (doubly refractive, therefore dark in phase (doubly refractive, therefore dark in phase microscopy) band bounded by two microscopy) band bounded by two isotropic (singly refractive, therefore light) isotropic (singly refractive, therefore light) bands. The bands. The anisotropicanisotropic band is called the band is called the A bandA band; the ; the isotropicisotropic band band is called the is called the I I band.band.

In the center of the A band, there is a In the center of the A band, there is a lighter region known as the H zone or lighter region known as the H zone or H H band.band.

The myofibrils are composed of The myofibrils are composed of proteinaceous structures called proteinaceous structures called myofilamentsmyofilaments..

These filaments are referred to as the These filaments are referred to as the thickthick filaments and filaments and thin thin filamentsfilaments

Thick filamentsThick filaments are made up of several are made up of several hundred hundred myosinmyosin molecules molecules

myosin moleculemyosin molecule has a has a tail regiontail region that is that is rodlike, and rodlike, and head regionhead region, with two globular , with two globular subunits projecting out at approximately subunits projecting out at approximately right angles with the filamentright angles with the filament

Note: Note: The thick filament is studded with The thick filament is studded with projections except at its center, which projections except at its center, which contains only myosin tails. Note that contains only myosin tails. Note that myosin molecules at opposite ends of the myosin molecules at opposite ends of the thick filament are oriented in opposite thick filament are oriented in opposite directions–sort of like a bundle of unsorted directions–sort of like a bundle of unsorted golf clubsgolf clubs

Each Each thin filamentthin filament contains three protein contains three protein molecules: molecules: actin, troponin, and actin, troponin, and tropomyosintropomyosin

T tubule is an T tubule is an invagination of the invagination of the muscle membrane, muscle membrane, forms a ring around forms a ring around every myofibril; every myofibril;

The position of the T The position of the T tubule with respect to tubule with respect to the sarcomere is the sarcomere is somewhat species somewhat species specificspecific

The The sarcoplasmic reticulumsarcoplasmic reticulum is is made up of tubules that run made up of tubules that run parallel to the sarcomeres from parallel to the sarcomeres from T tubule to T tubuleT tubule to T tubule

The sarcoplasmic reticulum is a The sarcoplasmic reticulum is a sack with its ends expanded sack with its ends expanded (the (the cisternaecisternae) adjacent to the ) adjacent to the T tubules and with narrow, T tubules and with narrow, longitudinal channels longitudinal channels connecting these expansions, connecting these expansions, one at each endone at each end

The Sliding Filament TheoryThe Sliding Filament Theory

Step 1: ACh released from presynaptic cleftStep 1: ACh released from presynaptic cleft

Step 2: Muscle cell (postsynaptic) is Step 2: Muscle cell (postsynaptic) is depolarizeddepolarized

Step 3: Depolarization propagates to the Step 3: Depolarization propagates to the Transverse TubuleTransverse Tubule

Step 4: Depolarized T-tubules trigger Step 4: Depolarized T-tubules trigger release of Calcium from sarcoplasmic release of Calcium from sarcoplasmic reticulumreticulum

Step 5: calcium binds to troponin, the positions Step 5: calcium binds to troponin, the positions of troponin and tropomyosin are altered on the of troponin and tropomyosin are altered on the the thin flament and myosin then has access to the thin flament and myosin then has access to its binding site on actinits binding site on actin

Step 6: Myosin hydolyzes ATP and undergoes a Step 6: Myosin hydolyzes ATP and undergoes a conformational change into a high-energy state. conformational change into a high-energy state. The head group of myosin binds to actin forming The head group of myosin binds to actin forming a cross-bridge between the thick and thin a cross-bridge between the thick and thin filaments. filaments.

Step 7: The resulting relaxation of the myosin Step 7: The resulting relaxation of the myosin molecule entails rotation of the globular head, molecule entails rotation of the globular head, which induces longitudinal sliding of the which induces longitudinal sliding of the filaments.filaments.

Step 7: The energy stored by myosin is Step 7: The energy stored by myosin is released, and ADP and inorganic released, and ADP and inorganic phosphate dissociate from myosinphosphate dissociate from myosin

Step 8: When the calcium level decreases, Step 8: When the calcium level decreases, troponin locks tropomyosin in the blocking troponin locks tropomyosin in the blocking position and the thin filament slides back position and the thin filament slides back to the resting state.to the resting state.

ENDEND

A.A. Ca++ removed from sarcoplasmCa++ removed from sarcoplasmB.B. Ca++ bound by troponinCa++ bound by troponinC.C. Arrival of motoneuron action potentialArrival of motoneuron action potentialD.D. Depolarization of T tubulesDepolarization of T tubulesE.E. Release of inhibition of myosin-ATPaseRelease of inhibition of myosin-ATPaseF.F. Action potential propagates along sarcolemmaAction potential propagates along sarcolemmaG.G. Cooperative configurational change in troponin Cooperative configurational change in troponin

and tropomyosinand tropomyosinH.H. Link between thick and thin filaments, swivel of Link between thick and thin filaments, swivel of

myosin headmyosin headI.I. Ca++ released into sarcoplasm from Ca++ released into sarcoplasm from

sarcoplasmic reticulumsarcoplasmic reticulumJ.J. Cross-bridges disconnectedCross-bridges disconnected

Arrival of motoneuron action potentialArrival of motoneuron action potential Synaptic transmission at neuromuscular junctionSynaptic transmission at neuromuscular junction Action potential propagates along sarcolemmaAction potential propagates along sarcolemma Depolarization of T tubulesDepolarization of T tubules Ca++ released into sarcoplasm from sarcoplasmic reticulumCa++ released into sarcoplasm from sarcoplasmic reticulum Ca++ bound by troponinCa++ bound by troponin Cooperative configurational change in troponin and tropomyosinCooperative configurational change in troponin and tropomyosin Release of inhibition of myosin-ATPaseRelease of inhibition of myosin-ATPase Link between thick and thin filaments, swivel of myosin headLink between thick and thin filaments, swivel of myosin head Tension exertedTension exerted Shortening by sliding filamentShortening by sliding filament Ca++ removed from sarcoplasmCa++ removed from sarcoplasm Mg++ATP bound by actinomyosinMg++ATP bound by actinomyosin Cross-bridges disconnectedCross-bridges disconnected Actinomyosin-ATPase inhibitedActinomyosin-ATPase inhibited Active tension disappearsActive tension disappears Series elastic elements restore resting lengthSeries elastic elements restore resting length