1. Nerve and Muscle
Physiology of nerve

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

3. Types of nerve fibers a- 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

4. 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

5. 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

6. 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

7. 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

8. Strength –Duration Curve
Stimulus amplitude
chronaxie 2R
Utilization time R
duration

9. 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

10. 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

11. 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

12. 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

13. Potassium equilibrium
-90 mV

14. 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

15. 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

16. Action Potential
Definition: It is the rapid change in membrane potential following stimulation of the nerve by a threshold stimulus.
Recording: microelectrodes and oscilloscope.

17. Membrane Permeabilites
AP is produced by an increase in Na+ permeability.
After short delay, increase in K+ permeability.
Figure 7-14

18. 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

19. 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
+35
-65
-90
overshoot
depolarization
repolarization mv FL
hyperpolarization
Latent period
time

20. Duration of Action Potential
Spike lasts 2msec
Hyperpolarization msec

21. 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

22. The Action Potential
A 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.

23. The Action Potential 1-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

24. The Action Potential
Within 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

25. The Action Potential
The 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)

26. 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.

27. Action potential initiation
S.I.Z.

28. Action potential termination

29. 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

30. 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

31. 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

32. 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

33. 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.

34. Excitability changes during the action potential
Up to FL, excitability increases
The 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.
ARP
RRP FL
Increased excitability

35. 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

36. Accommodation of nerve fiber
Slow increase in the stimulus intensity gives no response:
1- inactivation of Na+ Channels
2- opening of K+ Channels

37. 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

38. 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

39. Importance of saltatory conduction:
↑velocity of nerve conduction.
Conserve energy for the axon.

40. 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

41. 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

42. 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)

43. 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

44. 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

45. Nerve fiber types According to their thickness, they are divided into:
diameter
conduction
Spike duration
Remarks
A fibers
2-20 micron
20-120m/s
0.5 msec
Alpha, beta, gamma & delta
Most sensitive to pressure
B fibers
1-5 micron
5-15m/s
1msec
Preganglionic autonomic f
Most sensitive to hypoxia
C fibers
<1 micron
0.5-2m/s
2msec
Postganglionic autonomic f
Most sensitive to local anesthetics

46. 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

47. 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

48. 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

49. 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

50. 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

51. The sarcomere It is the functional unit of the muscle.
It ext\ends between two sheets called 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

52. Internal organization:

53. Striations:

54. 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.

56. 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

59. 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

60. Myosin thick filaments

61. Thin filaments
Backbone is formed of 2 chains of actin, forming helix, has active site, molecules
Tropomyosin: long filaments, located in the groove between the 2 chains of actin, covers the active sites, molecules.
Troponin: small, globular, formed of 3 parts; 1-TI TT TC
Actin tropomyosin Ca2+

62. α actinin binds actin to the Z line

64. 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 )Motor End Plate (MEP) )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
Now that I have given you some fundamental information necessary to understand synaptic transmission, I am going to talk about a well-known example of synaptic transmission and that is signaling at the NMJ.
The axon of a MN innervates the muscle at a specialized region of the muscle membrane called the end-plate. At this point the axon loses it myelin sheath and splits into many fine branches called synaptic buttons that contain nt to be released. Each button is positioned over a junctional fold of muscle membrane that express nt receptors. The pre and post synaptic membrane are separated by a synaptic cleft around 100nm wide.
The nt used at the NMJ is Ach. The enzyme Ache breaks down excess Ach that is present in the synaptic cleft.
When ACh is released, the membrane at the end-plate depolarizes and produces an EPSP called the end-plate potential. The EPP is large enough to open voltage-gated Na+ channels in the junctional folds. This converts the EPP into an AP.
The EPP was first studied by Fatz and Katz in the 1950’s using intracellular voltage recordings. They were able to isolate the EPP using the drug curare, which blocks AChR. They saw that the amplitude of the EPP was reduced below threshold for producing an AP. They also found that the synaptic potential was largest at the end-plate and decreased progressively as you moved further away.
end plate

66. 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

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

68. Myasthenia Gravis (MG)
Serious may be fatal disease of neuromuscular junction
Characterized 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

69. 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

70. Electrical changes Nerve action potential Muscle action potential RMP
-70mV
-90mV
Rate of conduction
According to myelination
5m/sec
duration
shorter
longer
After AP
Release of acetyl choline
Contraction after 2msec
+35
+35
-70
-90

71. 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
Mechanical changes AP

72. 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

73. 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

74. 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
Mechanical changes AP

76. 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

77. Action Potentials and Muscle Contraction

78. Mechanism of muscle contraction

79. Cross-bridge formation:

80. 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

81. 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