Cell Physiology 2

Cell Physiology Neuromuscular and Synaptic Transmission, Skeletal Muscle, Smooth Muscle Lectured by Bien Eli Nillos, MD

Neuromuscular and Synaptic Transmission  An action potential in the presynaptic cell causes depolarization of the presynaptic terminal  As a result of the depolarization, Calcium enters the presynaptic terminal causing release of neurotransmitter into the synaptic cleft

SYNAPSE

Presynaptic cell

Synaptic cleft

Postsynaptic cell

 Neurotransmitter diffuses across the synaptic cleft and combines with receptors on the postsynaptic cell membrane  Cause change in its permeability to ions and a change in its membrane potential

SYNAPSE

Presynaptic cell

Postsynaptic cell

Neuromuscular Junction  Synapse between axons of motor neurons and skeletal muscle  Acetylcholine – neurotransmitter released from the presynaptic terminal  Nicotinic receptor – found at the postsynaptic terminal, specific for Ach  Choline acetyltransferase – catalyzes the formation of Ach from acetyl coenzyme A and choline in the presynaptic terminal.

 Depolarization of the presynaptic terminal opens Calcium channels.  Calcium uptake causes release of Ach into the synaptic cleft.  The nicotinic Ach receptor is also a Na+ and K+ ion channel (e.g. ligand-gated channel)  Because the channels opened by Ach conduct both Na and K ions, the postsynaptic membrane potential is depolarized.

Presynaptic cell

SYNAPSE

Ca Ca

+ + + - - -

Postsynaptic cell

 Once the end plate is depolarized, local currents cause depolarization and action potentials in the adjacent muscle tissue.  Action potentials in the muscle are followed by contraction.  Ach is degraded to acetyl-CoA and choline by acetylcholinesterase on the muscle end plate.

Presynaptic cell

SYNAPSE

Ca Ca +++ + + + - - ----

Postsynaptic cell

 Myasthenia gravis – caused by antibodies to the ACh receptors  Characterized by skeletal muscle weakness and fatigability resulting from a reduced number of ACh receptors on the muscle end plate.  Treatment with AChE inhibitors prevents the degradation of ACh and prolongs the action of ACh at the muscle end plate.

Summation at Synapses  Spatial summation – occurs when two excitatory inputs arrive at a postsynaptic neuron simultaneously. They produce greater depolarization.  Temporal summation – occurs when two excitatory inputs arrive at a postsynpatic neurons in rapid succession; they add in stepwise fashion.

Neurotransmitters  Norepinephrine  Epinephrine  Dopamine  Serotonin  Histamine  Glutamate  GABA  Glycine

The Skeletal Muscle  Skeletal muscles are composed of masses of fibers, each an individual cell.  Muscles are composed of muscle fibers; fibers are composed (in part) of myofibrils; and myofibrils are composed of myofilaments.

 Each muscle fiber contains about 1000 myofibrils that are 1 m in diameter and run the length of the fiber.  Myofibrils have no membrane, being simply surrounded with cytoplasm.  The cross-striations of the myofibrils are serially repeating units called sarcomeres

 A sarcomere is bounded on each end by a disc, called the Z disc or Z line.  Each sarcomere contains an anisotropic (doubly refractive, therefore dark in phase microscopy) band bounded by two isotropic (singly refractive, therefore light) bands. The anisotropic band is called the A band; the isotropic band is called the I band.

 In the center of the A band, there is a lighter region known as the H zone or H band.  The myofibrils are composed of proteinaceous structures called myofilaments.  These filaments are referred to as the thick filaments and thin filaments

 Thick filaments are made up of several hundred myosin molecules  myosin molecule has a tail region that is rodlike, and head region, with two globular subunits projecting out at approximately right angles with the filament

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

 Each thin filament contains three protein molecules: actin, troponin, and tropomyosin

 T tubule is an invagination of the muscle membrane, forms a ring around every myofibril;  The position of the T tubule with respect to the sarcomere is somewhat species specific

 The sarcoplasmic reticulum is

made up of tubules that run parallel to the sarcomeres from T tubule to T tubule  The sarcoplasmic reticulum is a sack with its ends expanded (the cisternae) adjacent to the T tubules and with narrow, longitudinal channels connecting these expansions, one at each end

The Sliding Filament Theory Step 1: ACh released from presynaptic cleft Step 2: Muscle cell (postsynaptic) is depolarized Step 3: Depolarization propagates to the Transverse Tubule Step 4: Depolarized T-tubules trigger release of Calcium from sarcoplasmic reticulum

 Step 5: calcium binds to troponin, the positions

of troponin and tropomyosin are altered on the the thin flament and myosin then has access to its binding site on actin  Step 6: Myosin hydolyzes ATP and undergoes a conformational change into a high-energy state. The head group of myosin binds to actin forming a cross-bridge between the thick and thin filaments.  Step 7: The resulting relaxation of the myosin molecule entails rotation of the globular head, which induces longitudinal sliding of the filaments.

 Step 7: The energy stored by myosin is released, and ADP and inorganic phosphate dissociate from myosin  Step 8: When the calcium level decreases, troponin locks tropomyosin in the blocking position and the thin filament slides back to the resting state.

END

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Ca++ removed from sarcoplasm Ca++ bound by troponin Arrival of motoneuron action potential Depolarization of T tubules Release of inhibition of myosin-ATPase Action potential propagates along sarcolemma Cooperative configurational change in troponin and tropomyosin Link between thick and thin filaments, swivel of myosin head Ca++ released into sarcoplasm from sarcoplasmic reticulum Cross-bridges disconnected

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