Nerve and Muscle

Physiology of nerve

The neuron• The basic structural unit of the nervous system.• Structure: • The soma• The dendrites: antenna like processes• The axon: hillock, terminal buttons

Types of nerve fibersa- myelinated nerve fiber:• Covered by myelin sheath, protein-lipid layer,

secreted by Schwann cells,

acts as insulator to ion flow,

interrupted at Nodes of Ranvier

b- unmyelinated nerve fiber:• Less than 1μ, covered only with Schwann cells, as

postganglionic fibers

Electrical properties of a neuron• Electrical properties of nerve & muscle are:

• 1-There is difference in electrical potential between the inside and outside the membrane

• 2-Excitability: the ability to respond to any stimulus by generating action potential

• 3-Conductivity: the ability to propagate action potential from point of generation to resting point

Membrane potential; the basis of excitability• Def: electrical difference between the inside & outside the

cell• Causes: selective permeability of the membrane• more K+, Mg2+, Ptn, PO4 inside• more Na+, Cl-, HCO3-outside• Exists in all living cells & it is the basis of excitability• Excitability:• Def: it is the ability to respond to stimuli (change in the

environment) giving a response• The most excitable tissues are nerves & muscles• Stimuli:• Types:• Electrical (preferred), chemical, mechanical, or thermal.• Cathode ( more important) & anode

+anode -cathode

Excitability • Factors affecting effectiveness of the stimulus:• 1- strength: • effective stimulus• 2- duration:• a certain period of time, very short duration can not excite the

nerve• 3- rate of rise of stimulus intensity:• Rapid increase…. Active response• Slow increase …. adaptation

Strength –Duration Curve• Within limits stronger intensity shorter duration• Strength:• Threshold stimulus (rheobase): it is the minimal amplitude

of stimulus that can excite the nerve and produce action potential.

• Subthreshold stimulus: causes local response (electrotonic)

• Duration: • stimuli of very short duration can not excite the nerve• Utilization time: is the time needed by threshold stimulus

(Rheobase) to give a response• :Chronaxie time needed by a stimulus double the

rheobase to excite the nerve, it is a measure of excitability, decrease chronaxie means increase excitability

Strength –Duration Curve

chronaxie

Utilization timeR

2R

Stim

ulus

am

plitu

de

duration

Measuring the membrane potential

Recording: by 2 micoelectrodes inserting one inside the fiber & the other on the surface & connected to a voltmeter through an amplifier

Types of membrane potential

• Membrane potential has many forms:

• 1- RMP

• 2- on stimulation;

• a) action potential if threshold stimulus

• b) localized response (electrotonic) if subthreshold stimulus

Resting membrane potential (RMP)

*definition: It is the difference in electrical potential between the inside and outside the cell membrane under resting conditions with the inside negative to the outside

• Value:-90 mv large fibers, -70 in medium fibers, -20 in RBCs• Causes • 1- selective permeability• 2- Na-K pump

Recording: by 2 micoelectrodes inserting one inside the fiber & the other on the surface & connected to a voltmeter

Resting Membrane Potential

Selective permeability of the membrane: contributes to -86mv K+, ptn-, Mg2+&PO4- are concentrated inside the cell Na+, Cl-, HCO3- are found in the extracellular fluid During rest the membrane is 100 times more permeable to K+ than to Na+, K+tend to move outward through INWARD RECTFIER K+ channels down

their concentration gradient The membrane is impermeable to intracellular Ptn-&other organic ions Accumulation of +ve charges outside & -ve charges in At equilibrium :K+ in to out is 35:1 Na+ in to out is 1-10

Potassium equilibrium-90 mV

Na-K pump

• Definition: carrier protein on the cell membrane:

• 3 binding sites inside for Na+• 2 sites outside for K+• 1 site for ATP• Inner part has ATPase activity• It is an electrogenic pump

Contributes for -4mv and helps to keep RMP

• Nernest equation• E for K = -61 log con inside/ conc outside

=- 94• E for Na = -61 log con inside/ conc outside

=+ 61• Goldman equation: it considers• 1- Na, K and cl concentrations.• 2- K permeability is 100 times as that for

Na

Action Potential

• Definition: It is the rapid change in membrane potential following stimulation of the nerve by a threshold stimulus.

• Recording: microelectrodes and oscilloscope.

Membrane Permeabilites

• AP is produced by an increase in Na+

permeability.• After short delay,

increase in K+

permeability.

Figure 7-14

Shape and Phases of Action Potential

• 1- Stimulus artifact.: small deflection indicates the time of application of stimulus, it is due to leakage of current

• 2- Latent Period: isoelectrical interval, time for AP to travel from site of stimulation to recording electrode.

• 3- Ascending limb (depolarization):starts slowly from -90, till firing level-65mv, reaches &overshoots the isopotential, ends at +35

• 4- Descending limb:(repolarization):

starts rapidly till 70% complete then slows down

* Hyperpolarization: in the opposite direction

slight & prolonged • 5- RMP

Shape and Phases of Action Potential

1- Ascending limb

(depolarization)

Slow..firing level..rapid.

2- Descending limb

(repolarization)

rapid then slow

3- Hyperpolarization:

slight & prolonged

4- RMP

FLhyperpolarization

overshoot

depolarization repolarization

+35

0

-65

-90

time

mv

Latent period

Duration of Action Potential

• Spike lasts 2msec

• Hyperpolarization 35-40msec

Ionic basis of action potential• Depolarization is caused by Na+ inflow• Repolarization is caused by K+ outflow

Two types of gates:

1- voltage gated Na+ channels; having 2 gates: outer activation gate & inner inactivation gate

2- voltage gated K+ channels; one activation gate

When the nerve is stimulated::

a- the outer gate of VG Na+ opens, activating Na+ channel…. Na+ inflow

b- the inner gate of Na+ channels closes, inactivating Na+ channels… stop Na inflow

c- K+ gates open, activating K+ channels, K+ outflow

The Action PotentialA stimulus opens activation gate of some Na+ channels depolarizing membrane potential, allowing some Na to enter, causing further depolariztion

If threshold potential is reached, all Na+ channels open, triggering an action potential.

The Action Potential1-Depolariztaion:occurs in 2 stages:

Slow stage: -90 to -65mv: some Na+ channels opened, depolarizing membrane potential, allowing some Na to enter, causing further depolarization

At -65mv, the firing level or threshold for stimulation, all Na+ channels open, triggering an action potential.

Rapid stage: -65 to +35: all Na+ channels are opened, Na+ rush into the fiber, causing rapid depolarization

The Action PotentialWithin a fraction of msec, Na+ channel inactivation gates close and remained in the closed state for few milliseconds, before returning to the resting state.

2- Repolarization: Inactivation of Na+ channels and activation of K+ channels are fully open.

Efflux of K+ from the cell drops membrane potential back to and below resting potential

3- Hyperpolarization; slow closure of K+ channels

The Action PotentialThe Na+ & K+ gradients after action potential are re-established by Na+/K+ pump

Only very minute fraction of Na+ & K+ share in action potential from the total concentration

The action potential is an all-or-none response. (provided that all conditions are constant, AP once produced, is of maximum amplitude, constant duration & form, regardless the amplitude of the stimulus , however threshold or above

Action potential will not occur unless depolarization reaches the FL (none)

Action potential size is independent of the stimulus and once depolarization reaches FL, maximum response is produced, reaches a value of about +35 mV(all)

The Action Potential

Both gates of Na+ channel are closed but K+ channels are still open.

Continued efflux of K+ keeps potential below resting level.K+ channels finally close and Na+ channel

inactivation gates open to return to resting state.

Action potential initiation

S.I.Z.

Action potential termination

Action potential in a nerve trunk

• Nerve trunk is made of many nerve fibers

• The AP recorded is compound action potential, having many peaks

• The individual fibers vary in:

• 1- threshold of stimulation

• 2-distance from stimulating electrode

• 3- speed of conduction

• During depolarization, there is +ve feed back response.• Repolarization is due to:

1- inactivation of Na+ channels( must be removed before another AP

2- slower & more prolonged activation of K+ channels• Hyperpolarization (undershoot): slow closing of K+ channels, K+

conductance is more than in resting states• Role of Inward rectifier K+ channels:

Non gated channels

Tend to drive the membrane to the RMP

Drive K+ inwards only in hyperpolarization

Re-establishing Na+ &K+ gradient after AP:role of Na+ /K+ pump

All or none law

Electrotonic potentials & local response• Catelectronus: at cathode/ depolarization less than 7mV/ passive

• Anelectronus: at anode/ hyperpolarization/ passive

• Local response (local excitatory state):• Stonger cathodal stimuli• Slight active response• Some Na+ channels open, not enough to reach FL• It is graded• Does not obey all or none law• Non propagated• Excitability of the nerve increased• Caused by subthreshold stimulus • Can be summated & produce AP• Has no refractory period

Local Response (local excitatory change)

• Although subthreshold stimuli do not produce AP they produce slight active changes in the membrane that DO NOT PROPAGATE.

• It is a state of slight depolarization caused by subthreshold cathodal stimulus that opens a few Na channels not enough to produce AP

Local Response (local excitatory change)

• It differs from AP :

• It does not obey all or non rule

• Can be graded.

• Can be summated.

• It does not propagate.

Excitability changes during the action potential• Up to FL, excitability increasesThe remaining part of action potential, the nerve is refractory to stimulation (difficult to be restimulated)

• Absolute refractory period:Def: the period during which a 2nd AP can

not be produced whatever the strength of the stimulus

Length: from FL to early part of repolarization

Causes: inactivation of Na+ channels

• Relative refractory period: Def.; the period during which membrane

can produce another action potential, but requires stronger stimulus.

Length: from after the ARP to the end of the AP

Causes: some Na+ channels are still inactivated

K+ channels are wide open.

Increased excitability

ARP RRP

FL

Factors affecting Membane potential & Excitability

• Factors ↑ excitability:• * Role of Na+• 1) ↑ Na permeability (veratrine & low Ca 2+).

• Factors ↓ excitability:• 1)↓ Na permeability( local anaesthesia & high Ca2+) [ membrane

stbilizers]• Decrease Na+ in ECF: decreases size of AP, not affecting RMP• Blockade of Na+ channels by tetradotoxin TTX decrease excitability

& no AP• ** Role of K+:• 1)↑ K extracellularly (hyperkalemia).

• 2)↓ K extracellularly (hypokalemia): familial periodic paralysis

• 3) blockade of K+ channels by TEA: prolonged repolarization& absent hyperpolarization

• *** Role of Na+ K+ pump: only prolonged blockade can affect RMP & AP

Accommodation of nerve fiber

• Slow increase in the stimulus intensity gives no response:

• 1- inactivation of Na+ Channels

• 2- opening of K+ Channels

Conduction in an Unmyelinated Axon• The action potential generated at

one site, acts as a stimulus on the adjacent regions

• During reversal of polarity, the stimulated area acts as a current sink for the adjacent area

• A local circuit of current flow occurs between depolarized segment & resting segments (flow of +ve charges) in a complete loop of current flow

• The adjacent segments become depolarized, FL is reached, AP is generated

Figure 7-18

Conduction in Myelinated Axon (Saltatory conduction)

• Myelin prevents movement of Na+ and K+ through the membrane.

• The conduction is the same in unmyelinated nerve fibers Except that AP is generated only at Nodes of Ranvier

• AP occurs only at the nodes.– AP at 1 node depolarizes

membrane to reach threshold at next node.

• The +ve charges jump from resting Node to the the neighbouring activated one (Saltatory conduction).

Figure 7-19

Importance of saltatory conduction:

• ↑velocity of nerve conduction.

• Conserve energy for the axon.

Orthodromic & antidromic conduction

• Orthodromic: from axon to its termination

• Antidromic: in the opposite direction

• Any antidromic impulse produced, it fails to pass the 1st synapse & die out

Monophasic &biphasic AP

• Monophasic AP: recorded by one microelectrode inserted inside the fiber & one indifferent microelectrode on the surface.

• Biphasic: two recording electrodes on the outer connected to CRO

Depolarization & repolarization of a nerve fiber

• RMP does not record any change

• Depolarization flows to the +ve electrode ..... Upright deflection (+ve wave)

• Complete depolarization ... No flow of current (baseline)

• Repolarization to the +ve electrode....down deflection

• Complete repolarization ... No flow of current (baseline)

Action potential in a nerve trunk

• Nerve trunk is made of many nerve fibers

• The AP recorded is compound action potential, having many peaks

• The individual fibers vary in:

• 1- threshold of stimulation

• 2-distance from stimulating electrode

• 3- speed of conduction

Compound AP • Graded

• Subthreshold; no response occurs

• Threshold; a small AP, few nerve fibers

• Further increasing; AP amplitude increases up to a maximal

• Increasing the intensity, supramaximal stimuli, no more increase in the AP

Nerve fiber types

• According to their thickness, they are divided into:

diameterconductionSpike duration

Remarks

A fibers2-20 micron20-120m/s0.5 msecAlpha, beta, gamma & deltaMost sensitive to pressure

B fibers1-5 micron5-15m/s1msecPreganglionic autonomic fMost sensitive to hypoxia

C fibers<1 micron0.5-2m/s2msecPostganglionic autonomic fMost sensitive to local anesthetics

Metabolism of the nerve• Rest: nerve needs energy to maintain polarization of the

membrane, energy needed for Na+/K+ pump, derived from ATP. Resting heat

• Activity: pump activity increases to the 3rd power of Na+ concentration inside, if Na+ concentration is doubled, the pump activity increases 8 folds;23 .

• Heat production increases:• 1- initial heat during AP • 2- a recovery heat, follows activity =30 times the initial heat

• Neurotrophins:• Proteins necessary for neuronal development, growth & survival• Secreted by glial cells, muscles or other structures that neuron

innervate• Internalised & retrograde transported to the cell body

Types of muscles• Skeletal muscle: under voluntary control 40% of total body mass.• Cardiac muscle: not under voluntary control.• Smooth muscle: not under voluntary control. Both are 10% of total

body mass

Skeletal muscles

• Attached to bones• >400 voluntary skeletal muscles• Contraction depends on their nerve supply• 4 functions:• 1- force for locomotion & breathing• 2- force for maintaining posture & stabilizing joints• 3- heat production• 4- help venous return

Morphology

• Muscle fibers:• Bundled together by C.T.• Arranged in parallel between 2 tendenious ends• Is a single cell• Closely enveloped by glycoprotein sheath (sarcolemma)

outside the cell membrane• Made of many parallel myofibrils embeded in a

sarcoplasm, between a complex tubular system

Skeletal muscle• Each muscle fiber is a single unit. It is made up of many

parallel myofibrils embedded together and a complex sarcotubular system.

• Each muscle fibril contains interdigitating thick and thin myofilaments arranged in sarcomeres.

• 2 major proteins:• 1- thick filaments [myosin]• 2- thin filaments [actin, troponin, troopomyosin]• Troponin & trpomyosin regulate muscle contraction by

controlling the interaction of actin & myosin

The sarcomere• It is the functional unit of the

muscle.• It ext\ends between two

sheets called Z Z lines.• Thick filaments (Myosin) in the

middle (dark band (A)).• Thin filaments on both sides

(light band (I) ).• Z line in the middle of I band. • H zone in the middle of A

band.• When the muscle is stretched

or shortened, the thick & thin filaments slide past each other, and the I band increases or decreases in size

Internal organization:

Striations:

Myofilaments• 1- thick filaments (myosin):

• 300 myosin molecules

• 2 heavy chains & 4 light chains

• Each myosin molecule has two heads attached to a double chains forming helix tail.

• myosin head contain actin – binding site, an ATP- binding site and a catalytic site (ATPase).

• Each myosin head protrude out of the thick filaments forming cross bridges that can make contact with the actin molecule

• 2- Thin filaments (actin)

• Actin, tropomyosin, troponin.

• Actin is a double helix that has active sites for combines with myosin cross bridges.

• Troponin: 3 subunits I for Actin binding, T for tropomyosin binding, C for Ca binding.

Sarcotubular system• Consists of T-tubules and Sarcoplasmic reticulum.• T tubules consists of network of transverse tubules surround

each myofibril, at the junction of the dark and light bands.• T tubules are invaginations from cell membrane.• T tubules contain extracellular fluid.r• T tubules transmit the AP from the surface to the depth of the

muscle fiber.• Sarcoplasmic reticulum: surrounds each myofibril, run parallel to it• Sarcoplasmic reticulum: extends between the T tubules.• Sarcoplasmic reticulum: are the sites for Ca storage.• Sarcoplasmic reticulum ends expands to form terminal cistern,

which makes specialized contact with the T tubules on either side• Foot processes span the 200 A0 between the 2 tubules• SR contains protein receptor called Ryanodine that contains the

foot process and Ca channel• T tubule contains voltage- senstive dihydropyridine receptor that

opens the ryanodine channel

The muscle protein• Myosin protein:• Thick filaments: 300 myosin molecules• Myosin molecule is made up of 2 heavy chains coil around

each other to form a helix.• Part of the heliix extends to side to form an arm• Terminal part of the helix with 4 light chains combine to form 2

globular heads• The arm & head are called cross bridges, flexible at 2 hinges,

one at the junction between the arm leaves the body, the 2nd at the attachment of the head with the arm

• The myosin heads contain an actin –binding site, catalytic site for hydrolysis of ATP

Myosin thick filaments

Thin filaments

Backbone is formed of 2 chains of actin, forming helix, has active site, 300-400 molecules

Tropomyosin: long filaments, located in the groove between the 2 chains of actin, covers the active sites, 40-60 molecules.

Troponin: small, globular, formed of 3 parts; 1-TI 2-TT 3- TC

Actin tropomyosin Ca2+

• α actinin binds actin to the Z line

Neuromuscular Junction

• Def: it is the area lies between the nerve ending of the alpha motor neurons and skeletal muscle.

•Structure of the NMJ :

•1) terminal knobs 2)Motor End Plate (MEP) 3)Synaptic cleft

•contain Ach vesicle contain Ach receptors contain choline estrase

• Steps Of Neuromuscular Transmission:

•1) Arrival of action potential : ↑ permeability to Ca2+ .. Rupture of vesicles.

•2) Postsynaptic response: ↑ conductance to Na and K more Na influx…end plate potential

•3) EPP: graded, non propagated response that act as a stimulus that depolarizes the adjacent membrane to firing level… AP…. Muscle contraction.

•4) Acetyl choline degradation

end plate

Neuromuscular junction

• Properties of neuromuscular transmission:• 1) unidirectional: from nerve to muscle• 2) delay: 0.5msec • 3) fatigue: exhaustion of Ach vesicles.• 4) Effect of ions: ↑Ca….. ↑ release of Ach• ↑ Mg….↓ release of Ach• 5) Effect of drugs:

* Drugs stimulate NMJ• Ach like action Metacholine, carbachol, nicotine small dose.• inactivating choline esterase neostigmine, physostigmine,

diisopropyl phlorophosphate. * Drugs block NMJ: curare competes with Ach for its receptors

Motor end plate is a highly specialized region of the muscle plasma membrane.

Myasthenia Gravis (MG)

Serious may be fatal disease of neuromuscular junctionCharacterized by weakness of skeletal muscle, easy

fatigability may affect the respiratory muscles and cause death More in female It is suspected to be a type of autoimmunity (the patient

antibodies attack the acetyl choline receptors at the neuromuscular junction)

Treatment:Adminestration of drugs as neostigmine, inactivating

acetylcholinesterase

Changes that occurs in the skeletal muscle after its stimulation

1 -electrical changes: action potential

2 -Excitability changes: ends before the beginning of contraction

3 -chemical changes: at rest & during activity

4 -mechanical changes: contraction

Electrical changesNerve action potential Muscle action potential

RMP-70mV-90mV

Rate of conductionAccording to myelination5m/sec

durationshorterlonger

After APRelease of acetyl cholineContraction after 2msec

-70

+35

-90

+35

Excitability changes• It is like changes that occurs in the nerve during action potential (increased

excitability, ARP, RRP, Supernormal excitability, subnormal excitability, normal)

• The refractory period ends at the time of beginning of contraction, so during contraction, the excitability is normal, can respond to another stimuli

APMechanical changes

Electrical changes in the muscle

• Similar to nerve action potential:

• RMP: -90mv

• AP lasts 2-4msec &precedes muscle contraction by 2msec

• Single muscle fiber obeys all or none rule

Muscle Twitch a single action potential causes a brief contraction followed by

relaxation

The twitch starts 2msec after the start of depolarization, before the repolarization is complete

Excitability changes• It is like changes that occurs in the nerve (refractory) during action potential• The refractory period ends at the time of beginning of contraction, so during

contraction, the excitability is normal, can respond to another stimuli

APMechanical changes

Mechanical changes [excitation-contraction coupling]

Action potential produce muscle contraction in 4 steps;• 1- release of Ca2+: AP pass through T tubules,

causing Ca release from the terminal cistern into the cytoplasm

• 2- activation of muscle proteins: Ca2+ binds troponin, moves tropomyosin away from active site of actin, actin binds with myosin, contraction starts

• 3- generation of tension: binding, bending, detachment, return

• 4- relaxation: active process, when Ca is removed frrom the cytoplasm & actively pumped into the SR

Action Potentials and Muscle Contraction

Mechanism of muscle contraction

Cross-bridge formation:

Types of Muscle Contractions

• Isotonic: Change in length (muscle shortens) but tension constant

• Isometric: No change in length but tension increases e.g. Postural muscles of body

• Muscle contraction in the body is a mixture of both types e.g. when person lifts a heavy object, the biceps starts isometric, then isotonic contraction

Factors affecting muscle contraction• 1- type of muscle fiber:

• Slow red fiber: Slow contraction & relaxation, rich in myoglobin, not easily fatigued, adapted for prolonged weight bearing, e.g. soleus muscle

• Rapid pale fiber: rapid contraction & relaxation, poor myoglobin, easily fatigued, adapted for skilled movements, e.g. hands & extraocular muscles

• 2- type of load:

• Preload: load applied to the muscle before contraction changing its initial length, [within limits, the more the initial length, the more the tension in isometric contraction]

• Afterload: load added to the muscle after it starts contraction [the more the after load, the less will be the velocity of contraction

• 3- stimulus factor:

• Stimulus strength: the more strength of the stimulus, the more the fibers stimulated, the more force of contraction

• Stimulus frequency:

• low frequency; separate twitches

• Medium frequency; clonus

• High frequency; tetanus

• 4- fatigue: repeated stimulation of the muscle results in fatigue due to:

• Depletion of ATP,CP & glycogen consumption of acetyl choline

• Accumulation of metabolites decreased O2 & nutrient supply