Excitable Tissues PDF

Excitable Tissues Nerves and muscles are excitable tissues because they are able to respond to a change in surrounding environment (called stimulus) by changing the electrical properties of their cell membrane and generating impulses, and these impulses are used to transmit signals along the nerve...

Excitable Tissues Nerves and muscles are excitable tissues because they are able to respond to a change in surrounding environment (called stimulus) by changing the electrical properties of their cell membrane and generating impulses, and these impulses are used to transmit signals along the nerve or muscle membranes. “Nerve” Nerve cell (neurons): are the structural and functional units of the nervous system. 1 - The Cell Body 2 - Dendrites 3 - The Axon 4 - Axonal Terminals Myelin Sheath: Many nerve fibers are covered with a whitish, fatty (protein-lipid) sheath called the myelin sheath. Myelin protects and electrically insulates fibers from one another, and it increases the speed of transmission of nerve impulse. 1 Physiology of Cell membrane: The fluid which lies outside the cell membranes (ECF), differ in composition from that inside the cell (ICF). The cell membrane consists almost of a lipid bilayer, with large number of proteins molecule. The cell membrane act as a barrier for the movement of most water molecules and water soluble substance between ECF and ICF. Membrane potential caused by differences in the ions concentration on the two sides of the membrane caused by ion diffusion from its high concentration area to a lower concentration area. Figure: diffusion of solute from its high concentration area (left) to a lower concentration area (right). Movements of solutes or ions is due to concentration gradients. 2 Ion Channels: Plasma membranes are covered with a variety of ion channels made up of membrane proteins. Some of these channels are: 1. Leakage channels (passive):  Are always open.  Allow free movement of certain ions or molecules.  Tube-shaped channels from the extracellular (ECF) to the intracellular (ICF) ends.  Highly selective for the transport of one or more ions. 2. Gated channels (active): Gated channels have a molecular “gate”, usually one or more protein molecules that can change shape to open or close the channel in response to various signals a) Chemically-gated channels (Ligand): Open when the neurotransmitter binds e.g. Acetylcholine b) Voltage-gated channels: the gate responds to the electrical potential changes (voltage) across the cell membrane. Membrane potentials: 3   Polarized state (Resting membrane potentials): Definition: it is the difference in potential between the outer surface and the inner surface of the membrane of excitable tissues (nerve & muscle) under resting condition. The RMP of a nerve fiber is around –70 mv. That means, the potential inside the nerve fiber is 70 millivolt more negative than the potential in the extracellular fluid outside the fiber.  Depolarized state (depolarization): It is the reduction in membrane potential negativity (–60, –50, –40, ….+10, +20 …. mv), the inside of the membrane becomes less negative than the resting potential.  Hyperpolarized state (hyperpolarization): It is the increase in membrane potential negativity (–90, –100, …..mv), the inside of the membrane becomes more negative than the value of the resting potential. Factors determine RMP: 1. Passive Transport:  Selective permeability to potassium ions through Potassium “leak” channel.  These K+ leak channels may also leak Na+ ions slightly but are far more permeable to potassium than sodium (about 100 times).  The membrane is not permeable most of the negatively charged anions inside the cells especially proteins. This result in entrapment of protein anions inside the cell. 2. Active Transport of Sodium and Potassium Ions (Na+- K+ Pump):  This pump continually transports 3 sodium ions to the outside of the cell and 2 potassium ion to the inside. Because more positive charges are pumped to the outside than the inside, which causes a negative potential inside the cell membrane.  Note that this is an active transport of ions that requires energy that is provided from ATP by the activity of Na+- K+ ATPase enzyme. Figure: Na+- K+ Pump 4  Action potential Definition: it is a transient reversal in the membrane polarity of an excitable cell (nerve or muscle) in response to threshold stimulus. Phases and ionic basis: 1. Resting phase (Latent period):  It is the period from applying the stimulus until the response is produced. This is the resting membrane potential before the action potential begins.  The membrane is “polarized” during this stage –70 mVs. 2. Local excitatory state:  It is the period of depolarization where the membrane potential changes from -70 to – 55 mv.  It is caused by opening of voltage sensitive sodium channels.  During this period the amount of depolarization is proportionate to intensity of the stimulus and if the potential does not reach – 55 mv the potential produced remain local not propagated. 3. Depolarization phase:  It is the ascending limb of the spine or the upstroke where membrane potential is changed from -55 to +35.  At this stage, opening of voltage gated sodium channels allows positively charged sodium ions to rapidly diffuse to the interior of the axon. 4. Repolarization phase:  It is the descending limb of the spike or the down stroke where the membrane potential is returning to its resting value.  The sodium channels begin to close and the potassium channels open. 5. Hyperpolarization: some of the voltage gated K+ channels are still open with slow return to the close state. 6. The resting state: during which the Na+-K+ pump acts to restore ionic distribution. 5  –55 Excitability changes during action potential:  Absolute refractory period (ARP): During this period, the nerve excitability is completely lost (I.e. no stimulus can excite the nerve whatever its strength). It corresponds to the depolarization phase and early part of repolarization (ascending limb of depolarization and upper 1/3 of repolarization). It is due to inactivation of volt sensitive Na+ channels during this period.  Relative refractory period (RRP): during this period, nerve excitability is only partially recovered thus stronger stimulus than normal is required to excite nerve. It correspond to the remaining part 2/3 of the descending limb of repolarization. It is due to partial recovery of Na+ channels. 6 Local potential: It is a local partial non-propagated change in the membrane potential. The local response may be produced in neurons with subthreshold stimuli (local excitatory state). Action potential Graded potential (local response) Threshold stimulus Sub-threshold Its amplitude is 100 mv Its amplitude is 10 mv short duration 2-5 ms duration is long up to 1 minute Volt-sensitive sodium channels Ion channel involved Obeys All or Non Doesn’t obey Propagate Non propagated Excitability varies Excitability high Not summated Summated Has Refractory periods No refractory periods 7  All or None Low: If a single nerve fiber is stimulated with an inadequate (sub-threshold) stimulus no action potential only a local non-propagated change in the membrane polarity. Is a single nerve fiber is stimulated with an adequate (threshold) stimulus, an action potential will result. If a single nerve fiber is stimulated with a supra-threshold stimulus, an action potential will result which has the same characteristic. NOTE: Action potential has fixed amplitude independent of the strength of the stimulus above the threshold value. Increasing the intensity of stimulation can increase the frequency of identical action potential. It states that with the threshold stimulus a full action potential is produced. With stimuli higher than the threshold no change in action potential produced. With stimuli below the threshold no action potential is produced. 8 Propagation (conduction):  Conduction in unmyelinated fibers: The action potential moves along the axon as a wave of depolarization traveling away from the cell body. i.e. conduction occurs continuously from point to the next point, so it is slow about 0.5-2 m/sec.  Conduction in myelinated fibers: Myelin sheath is deposited around the axons by Schwann cells and oligodendrocytes which leaving small areas of axon uncovered and called “nodes of Ranvier”. Myelin sheath contains a lipid substance which decreases ion flow through the membrane. Therefore, action potentials occur only at nodes of Ranvier. The nerve impulse jumps along from node to the next node of Ranvier which is the origin of the term “salutatory conduction”. 9 Importance of salutatory conduction:  Increases the velocity of nerve transmission in myelinated fibers (100 m/sec).  Conserves energy.  Rapid repolarization. Factors affecting conduction velocity:  Type of nerve fiber: o Fibre diameter the velocity of conduction is directly proportional to nerve fiber diameter. o Thickness of myelin sheath. The thicker the fiber, the higher the velocity of conduction  Temperature also affects conductivity as the increase in temperature increases conductivity. Types of nerve fibers: Type A: has the largest diameter and highest velocity of conduction. Subtypes are alpha, beta, gamma, and delta. Type B: has a moderate diameter and moderate velocity of conduction. Type C: has the smallest diameter and the lowest velocity of conduction. 10  Muscular Tissue Types of muscular tissue: Skeletal Muscles Cardiac Muscle Smooth Muscles Types Site Muscles attached to heart GIT (peristalsis bone movement) Nuclei Multinucleated cell Uni- or Bi- nucleated Uninucleated cell Striated Striated Striated Unstriated Contraction Voluntary Involuntary Involuntary Rapid Medium speed Slow-wave like ** Striated: striped appearance because of the orderly arrangement of the thin and thick filaments. Physiological anatomy of skeletal muscle: Muscle Fascicle Muscle Fiber (muscle cell) Myofibril Thin and thick filaments (actin and myosin filaments). 11 Myofibril contains the main contractile proteins which are arranged as:  Thick filaments (myosin): It is composed of o Myosin tail. o Myosin head (cross-bridges): which contains:  an actin-binding site.  ATP binding site.  Catalytic site that hydrolyzes ATP.  Thin filaments: which made up of: o Actin: which has specific sites for binding with the cross-bridges of the myosin filaments. [active sites]. o Tropomyosin: binds to actin in order to covers the active sites on the actin under resting conditions. o Troponin: located along the tropomyosin molecules which has a regulatory function by binding to Ca2+.  Elastic filaments (Titin): it acts as a framework that lines up the actin and myosin filaments. Figure 1: Thick and thin filaments. 12 Figure 2: Thin filaments. 13 What is Sarcomere?? Sarcomere is the smallest functional (contractile) unit of muscular tissue. It is the portion of the myofibril that lies between two successive Z lines (Z-discs). The thick filaments are arranged in the middle of the sarcomere. The thin filaments are arranged at sides of the sarcomere and overlap part of the thick filaments. The amount of overlap between thick and thin filaments determines how much force the muscle will develop when stimulated. Figure 3: Sarcomere. Figure: relaxed and contracted sarcomere. 14 Transverse T-Tubules: It is an invagination of the surface of the muscle membrane and contains extracellular fluid. T-tubules help to carry electrical impulses deep within a muscle fiber and this allows the impulse to be brought very close to the sarcoplasmic reticulum throughout the fiber. Sarcoplasmic reticulum (SR): It is the endoplasmic reticulum of the muscle fibers. SRs surround the myofibril and run parallel to it. It has a high concentration of Ca++ which is used to initiate muscle contraction. Figure 4: A portion of myofibril shows T-tubules and sarcoplasmic reticulum. 15  Neuromuscular Transmission Neuromuscular transmission: Is transmission of impulses from motor neuron to skeletal muscle fibers. Neuromuscular junction: it is the place where the motor neuron axon connects to the muscle fiber. It contains:  Axon of motor neuron: contains acetylcholine (ACh) vesicles.  Motor end plate: this is a thickened membrane of muscle fiber and rich in Ach receptors.  Synaptic cleft: it is the extracellular space between the nerve terminals and muscle membrane which contains the enzyme acetylcholine esterase (AChase). Figure: Neuromuscular junction. 16 Steps of neuromuscular transmission: 1. An action potential travels along a motor nerve to its endings. 2. As the nerve impulse reaches the axon terminal, it increases the membrane permeability to Ca2+ through opening of voltage-gated calcium channels. Ca2+ enters the nerve endings and triggers exocytosis of the acetylcholine-containing vesicles. 3. At each ending, the nerve secretes a small amount of the neurotransmitter substance acetylcholine. 4. The acetylcholine binds to the nicotinic acetylcholine receptors at the motor end plate. The free Ach is hydrolysed by Ach esterase in the synaptic cleft. Degradation of Ach is necessary to prevent it from causing excessive muscle stimulation. 5. Opening of the acetylcholine-gated channels (ligand gated Na+ channels) allows large quantities of sodium ions to flow to the interior of the muscle fiber membrane. This initiates an action potential in the muscle fiber. 6. The action potential travels along the muscle fiber membrane in the same way that action potentials travel along nerve membranes. 7. The action potential depolarizes the muscle membrane (sarcolemma membrane). Such response is called motor end plate potential (EPP). It is important to know that motor end plate potential is a graded potential. And much of the potential electricity also travels deeply within the muscle fiber. Here it causes the sarcoplasmic reticulum to release large quantities of calcium ions that have been stored within this reticulum. 8. The calcium ions initiate attractive forces between the actin and myosin filaments, causing them to slide alongside each other, which is the contractile process. 9. Mechanism of muscle relaxation: After a fraction of a second, the calcium ions are pumped back into the sarcoplasmic reticulum by the Ca2+ membrane pump (active reuptake), and they remain stored until a new muscle action potential comes along. This removal of the Ca2+ ions from the myofibrils causes muscle contraction to stop and troponin- tropomyosin complex will cover the binding sites and the actin myosin interaction will stop. Properties of Neuromuscular Transmission: 1. It is unidirectional. 2. There is a delay of about 0.5 msec. 3. Easily fatigued as a result of repeated stimulation due to exhaustion of Ach vesicles. 4. Effect of Ions: Ca++ increases release of Ach, while in presence of excess Mg++ the release of Ach is greatly decreased. 17  The neuromuscular junction is affected by many drugs:  Drugs that inhibit neuromuscular transmission: o Botulinum toxin: it inhibits the release of Ach. o Curare: it blocks the transmission by competitive inhibition at the cholinergic receptors. o Nicotine in large dose and succinylcholine: produce persistent depolarization.  Drugs that enhance (facilitate) neuromuscular transmission o Nicotine in small dose: stimulates the nicotinic receptors. o Cholineesterase inhibitors: - Reversible cholinestrase inhibitors: like neostigmine. - Irreversible cholinestarse inhibitors: Organic phosphorus compounds like DFP. Figure 5: ACh is released from axonal terminal of a motor neuron to the synaptic cleft. ACh binds to the ACh receptors at the motor end plate and that stimulates sodium channel opening and sodium influx. 18 Cross bridge cycle a- Resting state: In the relaxed state, ATP bound to the myosin head is partially hydrolysed to ADP + Pi. (M ADP Pi) b- In the presence of the elevated myoplasmic calcium, myosin binds to actin. c- Hydrolysis of ATP is completed causing a conformational change in the myosin molecule, which pulls the actin filament towards the center of the sarcomere. d- A new ATP binds to myosin causing release of cross bridge. Partial hydrolysis of the newly bound ATP recock the myosin head which is now ready to bind again and again. If the myoplasmic calcium levels are still elevated the cycle repeats. If myoplasmic calcium are low relaxation occurs. NB: Shortage of ATP during muscle contraction stops the cycle in step c with formation of permanent actin myosin complexes as occurs during death (rigor mortis). 19 Figure 6: Neuromuscular transmission. 20 Figure 7: action potential transmission in skeletal muscles. 21 Figure 8: Cross bridge cycle 22 Sliding filaments theory of contraction: During muscle contraction the thin actin filaments slide over the thick myosin filaments. Step 1: Binding: myosin head attached to actin. (High energy ADP +P) Step 2: Bending (Power stroke): tilting of myosin head by 45°. Step 3: Detachment: the cross bridge detaches when a new ATP binds to myosin. Step 4: Binding: Rising of myosin head occurs when ATP splits to ADP+P. 23 Factors affecting muscle contraction: 1. Initial muscle fiber length (length-tension relationship) “Starling’s Low”: When muscles contract they generate force (measured as tension or stress) and decrease in length. Starling’s low describes the effect of sarcomere length on the active tension developed by a contracting muscle fiber. At point e on the diagram, the actin filament has pulled all the way out to the end of the myosin filament with no actin-myosin overlap. At this point, the tension developed by the activated muscle is zero. Then, as the sarcomere shortens and the actin filament begins to overlap the myosin filament, the tension increases progressively until the sarcomere length decreases to the normal resting length. At point c, the actin filament has already overlapped all the cross-bridges of the myosin filament but has not yet reached the center of the filament. On further shortening, the sarcomere maintains full tension until point b at a sarcomere length of about 2.0 micrometers. At this point, the ends of the two actin filaments begin to overlap each other. As the sarcomere length falls from its normal resting length, at point a, the strength of contraction decreases. At this point, the two Z lines of the sarcomere about the ends of myosin filaments. Then, as contraction proceeds to still shorter sarcomere lengths, the ends of the myosin filaments are crumpled, and the strength of contraction decreases. This diagram demonstrates that maximum contraction occurs when there is maximum overlap between the actin filaments and the cross-bridges of the myosin filaments, and supports the idea that the greater the number of cross-bridges pulling the actin filaments, the greater the strength of contraction. Figure: length- tension diagram for a single sarcomere. 24  2. Type of muscle fiber. Type I “slow” Type II “Fast” “ red fibers” Type IIa Type IIb “ red fibers” “ white fibers” ATP source Oxidative Oxidative Glycolytic “anaerobic oxidation” ATP release Slow Fast Fast Contraction velocity Slow Fast Fast Mitochondria many many Few Fatigue Low “ maintaining intermediate High posture” Myoglobin High “ red fibers” high Deficit 3. Mechanical changes: Isotonic contraction Isometric contraction Muscle shortening No muscle shortening during contraction Fixed tension Max tension Against a light or moderate loads i.e. do Against a heavy load i.e. no work work Mechanical efficiency 40% -50% Mechanical efficiency = 0 i.e. part of energy converts to work, and i.e. all energy is lost as heat. others as heat loss. 25  Myasthenia Gravis It is a condition characterized by extreme muscular weakness. It is an autoimmune condition in which the body produces antibodies against its own motor end-plate nicotinic ACh receptors. These antibodies destroy the receptors. So, not all of the released ACh molecules are able to find a functioning receptor site to bind. As a result, much of the ACh is destroyed by AChE without ever having an opportunity to interact with a receptor site and contribute to EEP. Treatment: administration of a drug that reversibly inhibits AChE temporarily to increase the level of ACh at the motor end plates (neostigmine) or by inhibiting the immune response by immunosuppressant drugs. 26