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Generalized Cell is composed of nucleus, cytoplasm (contains organelles) and plasma membrane. Plasma membrane is mosaic of different proteins embedded in a phospholipid bilayer. Hydrophilic portions of both proteins and phospholipids are exposed to water. Hydrophobic portions are in the non aqueous environment inside the membrane.

Membrane proteins are either integral or peripheral. Integral proteins are transmembrane proteins which span the hydrophobic interior to function as channels or carriers while peripheral proteins are not embedded; they are attached to surface to function in enzymatic activity and structure.

Ion channels are classified according to the method of gating into:

Ungated (leak) channels: which are always open.
Voltage gated: which open or close in response to change in electricity.
Ligand gated: which open or close in response to a chemical substance.
Mechanically gated: which open or close in response to mechanical factors.

Membrane proteins function in transportation, enzymatic activities, receptor sites, intercellular junctions, cell-cell recognition, cytoskeletal and extracellular matrix attachment.


Plasma membranes are selectively permeable. Movement across plasma membrane is either passive or active process.

Passive processes:

1. Diffusion: Net movement of a substance down a concentration gradient (graded concentration change over a distance in a particular direction) which is a random molecular movement results from intrinsic kinetic energy and is affected by temperature and molecular size and it continues until a dynamic equilibrium is reached. There are several types of diffusion:
a. Simple diffusion: Nonpolar substances that are lipid soluble pass directly through lipid bilayer. Polar and charged particles can diffuse if they can fit through pores.
b. Osmosis: Is diffusion of a solvent through a selectively permeable membrane. Solution with a greater solute concentration than inside a cell is called hypertonic solution. Solution with a lower solute concentration than inside a cell is called hypotonic solution. Solution with the same solute concentration as inside a cell is called isotonic solution. Total concentration of all solutes in a solution is called osmolarity. Osmotic pressure is the amount of pressure required to prevent net movement of water into a solution.
c. Facilitated diffusion: Lipid insoluble molecules too large to diffuse through membrane pores can move passively with carrier molecules which is selective (specific) and limited by number of carrier molecules present (saturated).
2. Filtration: Water and solutes are forced through a membrane or capillary by hydrostatic pressure (pressure gradient pushes solute-containing fluid out).


Active Processes:
1. Active Transport: Cell uses energy to move substances across the membrane (transport molecules harvest energy from ATP to pump molecules against concentration gradients). There may be coupled systems (move more than one substance) like symport (same direction) and antiport (opposite direction like Sodium-Potassium Pump).

2. Bulk Transport:
a. Exocytosis: Substance is released from vesicle (membranous sac which fuses with plasma membrane and releases its contents to outside).
b. Endocytosis: Large substances progressively enclosed by membrane and taken into cell like phagocytosis (engulfing hard substances), pinocytosis (ingestion of fluids) and receptor-mediated endocytosis.

I. Nerve

Nerve cell is called neuron. There are 100 billion neurons (100 million) with different structure, chemistry and function. Neurons are the functional elements of nervous system while glia are the supporting elements. Glia are 10 times as many as neurons.
A neuron contains cell body (also called soma or perikaryon) and neurites which involve axons and dendrites. The term dendritic tree is a collective term for all neurites of a given neuron. The dendrites are small (usually less than 2 mm) and organized symmetrically (like antennae) and they conduct nerve impulse toward the cell body. The axon is larger (up to 1 meter in length) and it conducts the nerve impulse from the cell body to the axon terminal (also called telodendria). Each neuron has single axon (but that axon usually branches into several axon collaterals). Most axons are enveloped by myelin sheath to provide electrical insulation. Neural signals are either efferent (away from the cell body) or afferent (towards the cell body).

Types of glia in central nervous system (CNS):

a. Astrocytes:
1- They support the neurons
2- They make exchange between capillaries and neurons (provide nutrients and rid wastes)
3- They guide the migration and growth of young neurons
4- They transmit certain impulses in the brain (like neurons)
b. Microglia: They migrate toward injured or troubled neurons and transform into special type of macrophages. So they are the scavenger cells that get rid of microorganisms or neural debris.
c. Ependymal cells: They line the central cavities of brain and spinal cord
d. Oligodendrocytes: They are the myelinating glia in central neurons that form myelin sheath which wrap around the axons to function in insulation.
Types of glia in peripheral nervous system (PNS):
a. Schwann Cells:
1- They produce myelin sheath and neurilemma in peripheral neurons
2- They aid in regeneration of damaged peripheral nerve fibers
b. Satellite cells: They surround cell bodies in PNS and have many of the same functions as astrocytes in CNS.

Classification of nerves
1. Physioanatomic classification: Neurons are classified into afferent (sensory) and efferent (motor). The sensory and motor neurons are subdivided into somatic and visceral neurons. Somatic and visceral neurons are further subdivided into general and special neurons.
2. Another classification is according to conduction velocity and diameter of nerve fiber. Nerve signal conduction velocity increases with increased diameter and presence of electrical insulation (myelin sheath). Classes are:
Nerve type Aα has the largest diameter and fastest conduction velocity e.g. somatic motor and proprioceptive nerve fibers.
Nerve type Aβ e.g. sensory fibers of fine touch and fine pressure.
Nerve type Aγ e.g. motor fibers to muscle spindle.
Nerve type Aδ e.g. sensory fibers of acute pain, crude touch and cold.
Nerve type B e.g. preganglionic autonomic nerve fibers.
Nerve type C has the smallest diameter unmyelinated fibers e.g. sensory fibers of chronic pain, heat, gross pressure and postganglionic sympathetic fibers.


Resting membrane potential
All living cells (animal and plant cells) have electrical potential difference across their plasma membranes. The membrane interior is negative in relation to the membrane exterior. This is called resting membrane potential (RMP) and it is due to different distribution of ions inside and outside the membrane.
IonExtracellularIntracellularNa+142 mEq/L10 mEq/LK+4 mEq/L140 mEq/LCl103 mEq/L4 mEq/LPhosphates4 mEq/L75 mEq/LProteins30 mg/dL200 mg/dL
RMP of nerve cell is 70 mV
RMP of skeletal muscle is 90 mV
RMP of cardiac muscle is 85 mV
RMP of smooth muscle is variable but nearly about 50 mV.
Causes of resting membrane potential:
Sodium-potassium pump: This is called Na+-K+-ATPase pump which extrudes three sodium ions outside the cell and intrudes two potassium ions inside. This results in much positive ions outside plasma membrane.
Fast sodium channels are closed at rest.
Continuous passive diffusion of K+ outside the cell. This diffusion potential is the major factor responsible for RMP.
Chloride ions stay inside the cell
Anionic (negatively charged) proteins and phosphates can not leave the cell due to their large size. See the figure in the next page

Action potential and Local responses
Nerve and muscle cells are excitable cells. When a sufficient external stimulus is applied on their plasma membrane, the negativity is reversed and the internal side will become positively charged. The external stimulus may be electrical, chemical, physical or other types of stimuli. This change in membrane potential is called action potential. The response in nerve cell is transmission of action potential (nerve impulse) while the response in muscle cell is contraction.

Action potential in neuron

-Subthreshold stimuli: When weak stimuli applied to the neuron, they may cause local responses but they dont cause action potential. Local responses may increase or decrease according to the strength of stimulus and they subside after removal of these stimuli. Local responses stay in their location and dont travel (no propagation).
-Threshold stimuli: When a sufficient stimulus raises the membrane potential 15 mV above RMP (i.e. from 70 mV to 55 mV); action potential phases will start and does not stop until complete cycle occurs. This is called all-or-none rule. The membrane potential at which action potential starts is called threshold potential or firing potential.
- Supramaximal stimuli induce the same effects as threshold stimuli and do not change the shape of action potential curve.
Phases of action potential curve in neurons
1-Depolarization phase: The plasma membrane loses its negativity with sharp rise of the curve toward zero potential and overshoots to reach about +35mV. This phase is due to opening of all fast Na+ channels with inrush of huge number of Na+ ions.
2-Repolarization phase: The plasma membrane returns to its negativity with rapid fall of the curve toward negative potential. This occurs due to fast inactivation of Na+ channels and continuous pumping of Na+ and passive diffusion of K+ outside the cell.
3-Hyperpolarization phase: Decline of the curve to a more negative potential than RMP which is here about 72 mV and it is due to slow closure of K+ channels.
After that, the membrane regains its RMP. See next page



Any stimulus, however large, does not induce any new action potential at time of previous depolarization until 2/3 repolarization is complete. This is called absolute refractory period. It occurs because the inactive Na+ channels cannot be reactivated before the last stage of repolarization or RMP.
From the point of 2/3 repolarization to the end of repolarization phase a stronger stimulus is needed to induce new, but weaker, action potential. It occurs because some inactive Na+ channels can now be activated. This is called relative refractory period.
Lack of Ca++ results in lower threshold potential which makes the membrane very excitable and continuously firing ﴾tetanus.﴿

Transmission of impulse (Propagation of action potential)

Action potential is triggered in axon hillock due to presence of large number of Na+ channels and transmitted along the axon. The huge number of positive charges inside the firing segment of membrane will be equilibrated by the adjacent segments resulting in electrotonic flow of current which is very fast (like in the wire of electricity).
Nerve fiber is not a solid wire, instead, it is leaky and surrounded by sea of electrolytes. So, the impulse will gradually subside unless there are new AP waves at the adjacent segments of the axon.

Every new wave will cost time (0.1 milliseconds for each AP) which will extremely delay the transmission of impulse. Myelin sheath provides insulation to prevent leakage of ions and, hence, increases conduction velocity.
Insulation is interrupted at regular intervals by nodes of Ranvier which act as augmentation stations to strengthen the ongoing wave of depolarization by triggering new AP waves because these nodes are rich in Na+ channels. This is called saltatory conduction because it is jumping from node to node
Saltatory conduction

It travels in only one direction from soma to axon terminal (orthodromic conduction) and not in the opposite direction (antidromic conduction) because when action potential leaves certain segment, it cannot return immediately to the same segment that passes an absolute refractory period. So, it proceeds forward to a new resting segment.

Synaptic and junctional transmission

Synapse is the junction between two neurons. The first is called presynaptic neuron and the other is called postsynaptic neuron. Between them is the synaptic cleft.


Synapses are either chemical or electrical. Electrical synapses are very rare in adult mammalian nervous system. Gap junction is an example of this type where current flows directly through a specialized protein molecule (connexon). The distance between two sides of membrane is very small (5nM).
Chemical synapses are the predominant type of synapses where chemical substances called neurotransmitters (NT) are synthesized and stored in synaptic vesicles.
When AP arrives at the axon terminal, it opens voltage gated Ca2+ channels (channels that are opened or closed electrically) and Ca2+ influx will increase intracellular Ca2+ concentrations which attract the synaptic vesicles (full of NT substance) to the presynaptic membrane and signals the NT to be released to the synaptic cleft by exocytosis.
Vesicles fuse with the active zones of presynaptic membrane. NT diffuses across the synaptic cleft to bind its specific receptor on the postsynaptic membrane.
Several types of neurotransmitters are available and each may have several types and subtypes of receptors. Postsynaptic action depends on the nature of the receptor. After that, NT must be inactivated by degradation, reuptake, diffusion, or bioconversion.

Properties of synapses:
One-way conduction from pre- to post-synaptic neurons
Synapse is a site of neurotransduction (from electrical to chemical signal).
Intercellular chemical message is converted into intracellular signal. The reaction between neurotransmitter and its specific receptor results in:
a. direct opening or closure of an ion channel
b. indirect opening or closure of an ion channel
c. initiation of various intracellular enzymatic or metabolic activities
d. induction of certain gene transcription (and protein production)
Synaptic potentials are either excitatory (EPSP) or inhibitory (IPSP). The EPSP bring the membrane potential toward threshold (depolarization) i.e. cations (+ve ions) enter the cell or anions (-ve ions) exit the cell. The IPSP causes hyperpolarization i.e. anions enter or cations exit.
EPSP and IPSP may be present simultaneously (at the same time) in the synaptic cleft. When EPSP is higher in magnitude there'll be postsynaptic stimulation. When IPSP is higher in magnitude there'll be postsynaptic inhibition.
Synaptic potentials are not all-or-none potentials. Greater stimulation results in greater potentials
A period of time (about 0.5 ms) is required for the signal to travel from pre- to post-synaptic neurons which is called synaptic delay.
Classification of neurotransmitters
Small molecule, rapidly acting transmitters:
Class I: Acetylcholine
ClassII: The amines (adrenaline "epinephrine", noradrenaline "norepinephrine", dopamine, serotonine and histamine).
Class III: Amino acids (GABA, glycine, glutamate and aspartate).
Class IV: Nitric oxide "NO".
Neuropeptide, slowly acting transmitters:
Hypothalamic-releasing hormones.
Pituitary peptides.
Peptides that act on gut and brain.
Peptides from other tissues.
Cholinergic neurons use acetyl-choline. Catecholinergic neurons use catecholamines (epinephrine, norepinephrine,..). Serotonergic neurons use serotonin. Amino acidergic neurons use amino acids, and so on...


Acetylcholine (Ach)
Acetylcholine (Ach) is the neurotransmitter for neuromuscular junction, preganglionic neurons of the sympathetic and parasympathetic PNS, postganglionic neuron of the parasympathetic PNS and basal forebrain and brain stem complexes. ACh is synthesized from acetyl coenzyme A and choline. The reaction is catalyzed by choline acetyl transferase enzyme (CAT). After doing its action on postsynaptic membrane, ACh must be degraded in the synaptic cleft by acetylcholinesterase enzyme (ACE).
ACh receptors are nicotinic receptors and muscarinic receptors. Nicotinic receptors are present in neuromuscular junction, sympathetic ganglia and many parts of CNS. Muscarinic receptors are present in smooth muscles and glands.

II. Muscle

A. Skeletal muscle: General functions of skeletal muscle are:
Movement, Maintenance of posture, Stabilization of joints and Temperature homeostasis
Muscle cell is the fiber. It is surrounded by sarcolemma (plasma membrane). There are inward invaginations from sarcolemma called T-tubules. Muscle fiber is also composed of sarcoplasmic reticulum SR (endoplasmic reticulum) which stores large amounts of Ca++ ions. The SR lie on both sides of T-tubules forming what is called sarcotubular system. The muscle fiber contains sarcoplasm (cytoplasm of muscle cells), myofibrils, multiple nuclei, mitochondria in addition to the other cellular components. Myofibrils are composed of myofilaments (thick and thin contractile elements of skeletal muscle which give the muscle its striation). The functional unit of skeletal muscle is called sarcomere.

Sarcomere

It is composed of the following compartments:
1. A bands (dark anisotropic bands) composed of myosin thick filaments.
2. I bands (light isotropic bands) composed of parts of actin thin filaments not overlapped by myosin.
3. H band (within A band) visible only in relaxed muscle.
4. M line (bisects H band).
5. Z disc (midline membrane in I band connecting myofibrils together).
So, sarcomere is region of myofibril between two successive Z discs.
Molecular composition of thick and thin myofilaments
Thick filaments: Myosin is rod like tail that terminates in two globular heads. Myosin heads contain ATP and inactive ATPase.
Thin myofilaments is comprised of G-actin (globular) arranged in double stranded helix and two regulatory proteins which are tropomyosin and troponin. Troponin-tropomyosin complex attached to actin filament and block myosin binding sites on actin filament.


Contraction of Skeletal Muscle
Sliding filament theory of Contraction (excitation contraction coupling)
1- Nerve impulse (action potential or AP) from motor neuron arrives motor end plate (neuromuscular junction) resulting in release of Ach into the synaptic cleft to bind nicotinic receptor on post synaptic membrane which opens Na+ channels and generates AP in sarcolemma.
2- AP propagates along sarcolemma and down T tubules resulting in release of Ca2+ from sarcoplasmic reticulum to the myofibrils.
3- Ca2+ binds to troponin.
4- Myosin ATPase is activated and ATP splits resulting in high energy myosin-ADP complex.
5- Myosin attaches to actin (formation of actin-myosin cross bridges).
6- ADP and inorganic phosphate are released from myosin.
7- Actin and myosin filaments slide along each other.
8- When new ATP attached to myosin heads, relaxation occurs.
9- The cycle is repeated until full contraction.
10- Ca2+ must be pumped back into sarcoplasmic reticulum (SR)
If Ca2+ does not return to SR abnormal contraction (contracture) occurs. After death, there is no ATP and muscle fibers cannot relax resulting in another sustained abnormal contraction called rigor mortis.
Motor unit
Motor unit is a single motor neuron plus its collaterals and skeletal muscle fibers they supply. Motor unit could be small in size (few muscle fibers) or large in size (large number of muscle fibers).
Stronger contraction requires larger number of successive AP, larger muscle mass and stimulation of more muscle fibers.
Smoother contraction requires gradual stimulation of motor units.
Fine precise contraction requires stimulation of small size motor units.
Gross contraction requires stimulation of large size motor unit.
Slow or fast contraction depend on the type of muscle fiber
Types of contraction
Muscle tension is the force of contracting muscle on an object. Load is the reciprocal force exerted by the object. To move a load, muscle tension must be greater than load. There are two types of contraction:
Isotonic contraction: Muscle changes in length and moves load.
Isometric contraction: Tension increases but the muscle length stays constant. The load is greater than force e.g. maintenance of posture.


Muscle metabolism
ATP is the sources of energy for muscle contraction are:
1. Little ATP which is stored within the muscle.
2. Direct phosphorylation of ADP to ATP by creatine phosphate
3. Anaerobic glycolysis: In the absence of oxygen, glycolytic products (pyruvic acid) are metabolized to lactic acid producing additional small quantities of ATP
4. Aerobic glycolysis: Provides 95% of ATP during light exercise. In presence of oxygen, products of glycolysis are broken down entirely with the generation of significant amounts of ATP.
5. Fatty acids are the major source of energy for resting muscle.
During exercise, extra-amount of oxygen is consumed to remove the excess lactate, replenish ATP and creatine phosphate stores and to replace myoglobin. This is called oxygen debt which is the explanation of pant. Exhaustion is a state of fatigue due to accumulation of lactates from anaerobic pathways resulting in decreased pH which inhibits the necessary reactions for muscle contraction.

B. Cardiac muscle

It is branched and interdigitated and functions as syncytium due to presence of intercalated discs and gap junctions. Its RMP is about -85 mV and its AP is slow (more than 200 milliseconds) and characterized by presence of plateau. The phases of AP in contractile cardiac muscle fibers are:
Phase 0: Depolarization lasts about 2 ms and occurs due to opening of all Na+ channels with huge influx of Na+ ions.
Phase 1: Initial rapid repolarization due to fast inactivation of Na+ channels.
Phase 2: Plateau lasts about 200 ms and occurs due to opening of Ca2+ channels and influx of Ca2+ ions.
Phase 3: Late rapid repolarization occurs due to closure of Ca2+ channels.
Phase 4: Base line (RMP)
Pacemaker potential
Cardiac muscle contraction is myogenic (originated inside the muscle) not neurogenic (initiated by nerve) and the nerve supply is only regulatory. This is due to the presence of specialized conductive tissue in the heart called pacemaker tissue. This tissue has unstable low membrane potential called prepotential or pacemaker potential which declines and depolarizes continuously and steadily due to slow influx of Na+ (and slow decrease in K+ efflux) which spreads the impulses all over the heart. Steeper prepotentials result in quicker heart rate (tachycardia), while lower prepotentials result in slower heart rate (bradycardia).

C. Smooth muscle

Small, spindle-shaped cells arranged in sheets of opposing fibers. Generally two sheets with fibers at right angles to each other longitudinal and circular layers. The alternating contraction of layers results in peristalsis. Smooth muscle lacks troponin complex and sarcomeres.
Electrical communication between individual smooth muscle cells (gap junctions) make the entire sheet responds to a single stimulus. Some tissue has pacemaker cells and some are self-excitatory.
The difference between smooth and skeletal is that Ca2+ interacts with regulatory molecules called calmodulin not troponin. Contraction is slow, sustained and resistant to fatigue. Smooth muscle has a unique property of depolarization and contraction in response to stretch.
Smooth muscle also has the property of stress-relaxation (plasticity). This property is of benefit especially in uterus in order to adapt to the continuous increase in fetal size and in urinary bladder to adapt to the continuous increase in urine volume.
Smooth muscles are in continuous state of partial contraction (tone). Nerve supply with multiple neurotransmitters is found in smooth muscles but its role is not to initiate muscle contraction, but to modify that muscle tone.
Smooth muscle is also affected by other factors like chemicals, pH, temperature, CO2, O2 ....etc. There are two types of smooth muscle:
Single-unit smooth muscle: Function as syncytium. Found mainly in the wall of hollow viscera.
Multi-unit smooth muscle: Has no gap junctions and each muscle works individually. Found in the iris of eye, vas deferens, epididymus, large pulmonary airways and large blood vessels. They have many functional similarities to skeletal muscles but irregularly and involuntarily contract with prolonged duration.


Comparison of skeletal, cardiac and smooth Muscle
CharacteristicSkeletalCardiacSmoothLocationAttached to bones, fascia and skinWalls of heartSingle-unit: visceral organs
Multi-unit: Internal eye muscles, large airways and arteriesAppearanceSingle, long, cylindrical, striated, multinucleateBranching chains of cells, uninucleate, striatedSingle, non-striated, uninucleateSarcomerePresentPresentNoneT-tubulesAt each endAt one endNoneGap junctionsNonePresentIn single-unitNeuromuscular junctionsPresentNoneIn multiunitRegulation of
contractionSomatic;
VoluntaryAutonomic, Pacemaker, Hormones; InvoluntaryAutonomic,
Hormones,
Local regulation,
Response to stretchCa2+ SourceSRSR, Extracellular SR, Extracellular Role of Ca2+Via troponinVia troponinVia calmodulinPacemakersNonePresentIn single-unitNervous ControlExcitationRegulationRegulationContraction SpeedVaries: slow to fastSlowVery slowRhythmicityNoneYesIn single-unitStretch EffectStrong contractionStrong contraction Stress-relaxation response (plasticity)Source of EnergyAerobic or anaerobicAerobicPrimarily anaerobic

Nerve and Muscle Professor Basim Zwain

- 1 -

L o c a l ↑↑ r e s p o n s e s ↑↑↑↑

Depolarization

Repolarization

Hyperpolarization


Overshoot of
depolarization

RMP

Threshold

1

2

Electrotonic flow of current




رفعت المحاضرة من قبل: Muhammed Jabir
المشاهدات: لقد قام 3 أعضاء و 168 زائراً بقراءة هذه المحاضرة








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