Skeletal & Smooth Muscle PDF

SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 OUTLINE The portion of a myofibril that lies between two successive Z...

SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 OUTLINE The portion of a myofibril that lies between two successive Z discs I. SKELETAL MUSCLE Myofibrils>muscle fiber>fascicle>muscle A. Sarcomere Myocytes called muscle fibers B. Muscle excitation C. Excitation contraction coupling Sarcolemma – cell membrane D. Muscle contraction Sarcoplasm – cytoplasm of cell E. Molecular Basis of Contraction F. Cross Bridge Cycling 1. Initiation of Cross Bridge Cycling at Rest 2. Formation of Actin-Myosin Complex 3. Power Stroke 4. Detachment of Myosin head of Cross bridge from the active site of an active filament 5. Reactivation of Myosin head G. Muscle contraction II. SMOOTH MUSCLE A. Types of Smooth Muscle B. Membrane potential and action potential C. Muscle contraction and relaxation COMPARISON OF SKELETAL AND SMOOTH III. MUSCLE IV. REVIEW OF NERVE ACTION POTENTIAL A. Ion Channels 1. Voltage-gated 2. Ligand-gated B. Diffusion Potential C. Equilibrium Potential D. Resting Membrane Potential E. Action Potential F. Formation of Action Potential G. Depolarization of the Action Potential H. Hyperpolarization and Return to Resting Potential I. Myelin and Propagation of action potential J. Nodes of Ranvier Z lines (“Zwischenscheibe”): borders M lines (“Mittelscheibe”): midline A band (“Anisotrophic”): Entire length of myosin H band (“Heler”): Inside A band, purely myosin, no actin interspersed Bare zone: Inside H band, no myosin heads I band (“Isotrophic”): Purely actin, no myosin interspersed A. Sarcomere The smallest functional unit of a skeletal muscle fiber and is a highly organized arrangement of contractile, regulatory, and structural proteins It is the shortening of these individual sarcomeres that lead to the contraction of individual skeletal muscle fibers (and ultimately the whole muscle) PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 C. Process of Excitation contraction coupling When end-plate potential reaches threshold level, it produces action potential which propagates over muscle fibre and through it along transverse tubules End plate potential- The sudden insurgence of sodium ions into the muscle fiber when the acetylcholine-gated channels open causes the electrical potential inside the fiber at the local area of the end plate to increase in the positive direction B. Process of muscle excitation as much as 50 to 75 millivolts, creating a local potential Muscle – excitable tissue When stimulated shows response o Electrical response – production of action potential o Mechanical response – contraction Difference between excitation of nerve and muscles Excitation – action potential Contraction – muscle contraction Linking of these 2 events is done by coupling done by Ca ions Ca ion is one of the most important ions in muscle contraction PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 D. Process of muscle contraction The initiation and execution of muscle contraction occur in the following sequential steps. An action potential travels along a motor nerve to its endings on muscle fibers. At each ending, the nerve secretes a small amount of the neurotransmitter substance acetylcholine. The acetylcholine acts on a local area of the muscle fiber membrane to open “acetylcholine-gated” cation channels through protein molecules floating in the membrane. Opening of the acetylcholine-gated channels allows large quantities of sodium ions to diffuse to the interior of the muscle fiber membrane. This action causes a local depolarization that in turn leads to opening of voltage-gated sodium channels, which initiates an action potential at the membrane. AP initiated in plasma membrane spread to surface and into muscle fibre through T tubules When reaches tip of T tubule activate voltage-gated DHP (Dihydropyridine Receptors) Ca ion get attached to troponin-C and starts chain of events So Ca acts as linkage between excitation and contraction process Ca ion get attached to Troponin-C & starts chain of events So Ca acts as linkage between excitation & contraction process Activated DHP receptors triggers opening of Ca release channels on terminal cisterns i.e. Ryanodine Receptors Ca diffuses into cytoplasm and ICF Ca increase (2000 times) PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 3. Power stroke 4. Detachment of myosin head of cross bridge from the active site of an Actin filament 5. Reactivation of Myosin Head E. Molecular Basis of Contraction A.F.Huxley & H.E.Huxley put forward o Sliding Filament theory or -in relaxed state: the ends of the actin filaments extending from two successive Z discs barely begin to overlap one another. -in contracted state: actin filaments have been pulled inward among the myosin filaments, so their ends overlap one another to their maximum extent. Also, the Z discs have been pulled by the actin filaments up to the ends of the myosin filaments o Rachet theory or o Walk-along theory or o Modern theory of Muscular Contraction 1. Initiation of Cross Bridge Cycling at Rest F. Cross Bridge Cycling Troponin I is lightly bound to actin & Myosin binding sites on actin is covered by tropomyosin which lies in a groove Steps in cross bridge cycling: between actin strands. Troponin T attached to tropomyosin to form troponin- 1. Initiation of cross bridge cycling tropomyosin complex. 2. Formation of Actin-myosin complex PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 After Excitation – Ca released in cytosol is attached to Troponin C. Causes conformational change & Tropomyosin to move laterally 3. Power Stroke Uncover active binding sites on Actin. Actin-Myosin-ADP-Pi complex triggers o Release of Pi & ADP o Conformational change in myosin & myosin head flex toward arm. This movements generate mechanical force – POWER STROKE 2. Formation of Actin-Myosin Complex Head of myosin binds with ATP ATPase activity of head of myosin breaks ATP into ADP + Pi cleavage products Head gets energy move perpendicular toward Actin & gets attached Effects of Power Stroke If load on muscle is small – Actin slides over myosin & muscle shortening If load is Large – flexion of myosin headstretching of elastic neck & no sliding PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 4. Detachment of Myosin Head of Cross Bridge from the Active Site of an Actin Filament Release of ADP & Pi make new ATP to attach to myosin head This new ATP with myosin head has low affinity for Actin so dissociation of myosin head with Actin occurs 5. Reactivation of Myosin Head This bound ATP splits again into ADP & Pi Which again give energy to myosin head & reactivate it Again energized, head move towards Actin filaments & gets attached to it G. Muscle Contraction Changes at Sarcomere Level During Muscle Contraction Width of A band remains constant H zone disappears I band width decreases Z line move closer The Sarcomere shortens Role of ATP in Muscle Contraction and Relaxation ATP hydrolysis gives energy to cross bridges -- provide force ATP binding to Myosin dissociate cross bridges & begin new cycle Ca ATPase by hydrolysis of ATP provide energy for Ca pump to transport Ca back – ending contraction & Muscle Relaxes When a muscle contracts, work is performed and energy is required. Large amounts of ATP are cleaved to form ADP during the contraction process, and the greater the amount of work performed by the muscle, the greater the amount of ATP that is cleaved; this phenomenon is called the Fenn effect. Steps in Muscle Relaxation 1. After a few ms Ca pump transport Ca from Sarcoplasm 2. Sarcoplasmic Reticulum discharge to Terminal Cisterns 3. Removal of Ca from Troponin 4. Rotate Troponin Tropomyosin Complex 5. Cover active sites, closes cross bridge cycle & relaxes Muscle PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 II. SMOOTH MUSCLE No Troponin Contains: o Myosin-light chain kinase (MLCK): phosphorylates and activates myosin heads o Myosin-light chain phosphatase (MLCP): dephosphorylates and inactivates myosin heads o Calmodulin: binds with Ca o Caldesmon and Calponin: inhibits muscle contraction o Dense Bodies: analogous to Z lines o Rudimentary SR o Rudimentary T-tubules (Caveoli) Present in the walls of hollow organs Controls movements of most organs A. Types of smooth muscle Contractile Response The smooth muscle of each organ is distinctive from that of Muscle stimulated -> Excited most other organs in several ways: Response – Contraction (1) physical dimensions, (2) organization into bundles or sheets, Manifested by (3) response to different types of stimuli, o Shortening (Iso-Tonic) (4) characteristics of innervation, and o Developing Tension (Iso-Metric) (5) function. o Both Yet, for the sake of simplicity, smooth muscle can generally be divided into two major types: multi-unit smooth muscle and unitary (or single-unit) smooth muscle. Types of muscle contraction B. Membrane potential and action potential More voltage-gated Ca channels as compared to voltage- gated Na channels Flow of Calcium ions into the cell is mainly responsible for generation of action potentials Calcium channels open slowly and remain open for a longer duration resulting in prolonged plateau of action potentials and muscle contraction Slow wave rhythm Not action potential itself Caused mainly due to slow and rapid pumping of positive ions, presumably Na+ Slow waves are also called “pacemaker waves” PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 C. Smooth Muscle Contraction and Relaxation 1. Hormones, NT, stretch triggers increased ICF Ca 2. ICF Ca binds with Calmodulin 3. Calcium-Calmodulin complex activates MLCK 4. MLCK phosphorylates (and activates) myosin heads 5. Activated myosin heads causes smooth muscle contraction 6. MLCP dephosphorylates (and inactivates) myosin heads 7. Inactivated myosin heads: causes smooth muscle relaxation o Chemical studies have shown that actin and myosin filaments derived from smooth muscle interact with each other in much the same way that they do in skeletal muscle. Further, the contractile process is activated by calcium ions, and adenosine triphosphate (ATP) is degraded to adenosine diphosphate (ADP) to provide the energy for contraction. Slowness of Onset of Contraction and Relaxation of the Total Smooth Muscle Tissue. A typical smooth muscle tissue begins to contract 50 to 100 milliseconds after it is excited, reaches full contraction about 0.5 second later, and then declines in contractile force in another 1 to 2 seconds, giving a total contraction time of 1 to 3 seconds. This is about 30 times as long as a single contraction of an average skeletal muscle fiber. However, because there are so many types of smooth muscle, con- traction of some types can be as short as 0.2 second or as long as 30 seconds. PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 IV. REVIEW OF NERVE ACTION POTENTIAL A. Ion channel cell membrane integral proteins that permit passages of certain ions selective, maybe open or closed Voltage-gated channels: opened or closed by changes in membrane potential e.g. activation vs inactivation gate of nerve Na channel When the inside of the membrane loses its negative charge, these gates would open suddenly and allow sodium to pass inward through the sodium pores. Ligand-gated channels: opened or closed by hormones, 2nd messengers, neurotransmitters e.g. skeletal muscle AchR (Nm receptor) that opens gate for Na and K when Ach binds One of the most important instances of chemical gating is the effect of acetylcholine on the so-called acetyl- choline channel. Acetylcholine opens the gate of this channel, providing a negatively charged pore about 0.65 nanometer in diameter that allows uncharged molecules or positive ions smaller than this diameter to pass through. This gate is exceedingly important for the transmission of nerve signals from one nerve cell to another. B. Diffusion Potential potential differences generated across a membrane because of a concentration difference of an ion C. Equilibrium Potential diffusion potential that exactly balances (opposes) the tendency for diffusion caused by concentration differences aka Nernst potential If an electrical potential is applied across the membrane, the electrical charges of the ions cause them to move through the membrane even though no concentration difference exists to cause movement. D. Resting membrane potential established by diffusion potentials resulting from III. COMPARISON OF SKELETAL AND concentration differences of various ions as each attempt to SMOOTH MUSCLE drive the membrane potential towards its equilibrium potential normal nerve RMP: -70mV E. Action Potential consists of rapid depolarization/upstroke (“ON”) followed by repolarization (“OFF”) An action potential elicited at any one point on an excitable membrane usually excites adjacent portions of the membrane, resulting in propagation of the action potential along the membrane. Action potentials are formed when a stimulus causes the cell membrane to depolarize past the threshold of excitation, causing all sodium ion channels to open. When the potassium ion channels are opened and sodium ion channels are closed, the cell membrane becomes hyperpolarized as potassium ions leave the cell; the cell cannot fire during this refractory period. The action potential travels down the axon as the membrane of the axon depolarizes and repolarizes. PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 Myelin insulates the axon to prevent leakage of the current as Neurotransmitter molecules bind to receptors located on a neuron’s it travels down the axon. dendrites; voltage-gated ion channels open Nodes of Ranvier are gaps in the myelin along the axons; Excitatory synapses: positive ions flood the interior of the neuron and they contain sodium and potassium ion channels, allowing the depolarize the membrane, decreasing the difference in voltage action potential to travel quickly down the axon by jumping between the inside and outside of the neuron from one node to the next. Stimulus from a sensory cell or another neuron depolarizes the target Nodes of Ranvier- unmyelinated part of axons neuron to its threshold potential (-55 mV), and Na+ channels in the axon hillock open, starting an action potential Sodium channels open, the neuron completely depolarizes to a membrane potential of about +40 mV. The action potential travels down the neuron as Na+ channels open. HYPERPOLARIZATION AND RETURN TO RESTING POTENTIAL Action potentials are considered an “all-or nothing” event --All-or-nothing principle. Once an action potential has been elicited at any point on the membrane of a normal fiber, the depolarization process travels 42 UNIT II Membrane Physiology, Nerve, and Muscle over the entire membrane if conditions are right, or it might not travel at all if conditions are not right. Threshold potential is reached, the neuron completely depolarizes When depolarization is complete, the cell “resets” its membrane voltage back to the resting potential. The Na+ channels close, beginning the neuron’s refractory period. F. FORMATION OF ACTION POTENTIAL During the resting state, before the action potential begins, the conductance for potassium ions about 100 times as great as the conductance for sodium ions. This is caused by much greater leakage of potassium ions than sodium ions through the leak channels. 1. A stimulus from a sensory cell or another neuron causes the target cell to depolarize toward the threshold potential. 2. If the threshold of excitation is reached, all Na+ channels open and the membrane depolarizes. 3. At the peak action potential, K+ channels open and K+ begins to leave the cell. At the same time, Na+ channels close. 4. The membrane becomes hyperpolarized as K+ ions continue to leave the cell. The hyperpolarized membrane is Sodium ions-depolarization in a refractory period and cannot fire. Potassium ions-repolarization and hyperpolarization 5. The K+ channels close and the Na+/K+ transporter restores the resting potential. G. MYELIN AND PROPAGATION OF THE ACTION POTENTIAL For an action potential to communicate information to another neuron, it must travel along the axon and reach the axon terminals where it can initiate neurotransmitter release. Speed of conduction of an action potential along an axon is influenced by both the diameter of the axon and the axon’s resistance to current leak. Myelin acts as an insulator that prevents current from leaving the axon, increasing the speed of action potential conduction. DEPOLARIZATION AND THE ACTION POTENTIAL PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 Arranged according to the sequence of Action Potential. A. A stimulus from a sensory cell or another neuron causes the target cell to depolarize toward the threshold potential. B. The membrane becomes hyperpolarized as K+ ions continue to leave the cell. The hyperpolarized membrane is in a refractory period and cannot fire. C. The K+ channels close and the Na+/K+ transporter restores the resting potential. D. At the peak action potential, K+ channels open and K+ begins to leave the cell. At the same time, Na+ channels close. E. If the threshold of excitation is reached, all Na+ channels open and the membrane depolarizes. TEST YOUR KNOWLEDGE 1. __________ activates myosin heads while ___________ H. NODE OF RANVIER inactivates myosin heads in smooth muscle. Natural gap in the myelin sheath along the axon A. Caldesmon; Calponin Unmyelinated spaces are about one micrometer long and B. Myosin-light chain phosphatase; Myosin-light chain kinase contain voltage gated Na+ and K+ channels C. Calmodulin; Calponin The flow of ions through these channels, particularly the D. MLCK; MLCP Na+ channels, regenerates the action potential over and over again along the axon 2. In cross bridge cycling, after excitation, Ca released in Action potential “jumps” from one node to the next in cytosol is attached to ________ saltatory conduction A. T tubules B. Troponin T C. Troponin C Saltatory conduction is of value for two reasons: D. Calmodulin Increased velocity -by causing the depolarization process to jump long intervals 3. All are true except: along the axis of the Membrane Potentials and 43 Action A. Width of A band remains constant Potentials nerve fiber, this mechanism increases the velocity B. H zone disappears of nerve transmission in myelinated fibers as much as 5- to C. I band width increases 50-fold. D. Z line move closer Energy conservation 4. What is an example of a multi-unit muscle? -conserves energy for the axon because only the nodes A. Bile duct depolarize, allowing perhaps a hundred times smaller loss of B. Intestine ions than would otherwise be necessary and therefore C. Uterus requiring little energy for re-establishing the sodium and D. Piloerector muscle potassium concentration differences across the membrane after a series of nerve impulses 5. What is responsible for generation of action potentials in smooth muscles? A. Ca influx B. Na influx C. K influx D. Ca binding to calmodulin 6. All are true except: A. Resting membrane potential of nerves is -70 while skeletal muscles is -90 B. When AP reaches tip of T tubules, activate voltage-gated Ca channels C. Sarcomere is the smallest functional unit of a skeletal muscle fiber D. I band (“Isotrophic”): Purely actin, no myosin interspersed PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.  SKELETAL & SMOOTH MUSCLE DR. KATHLEEN O. BALMILERO, MD, DPBA |10/06/2020 7. What is the sequence for cross-bridge linking? ____Power stroke Answers: D, C, C, D, A, B, B, C, A-E-D-B-C ____Detachment of myosin head of cross bridge from the active site of an Actin filament ____Formation of Actin-myosin complex ____Reactivation of Myosin Head REFERENCES ____Initiation of cross bridge cycling A. 3,4,5,2,1 1. Guyton and Hall, Textbook of Medical Physiology, 13 th Edition B. 3,4,2,5,1 C. 3,5,2,4,1 D. 3,2,5,4,1 8. What is the sequence for smooth muscle contraction and relaxation? ____ICF Ca binds with Calmodulin ____Inactivated myosin heads: causes smooth muscle relaxation ____Calcium-Calmodulin complex activates MLCK ____Hormones, NT, stretch triggers increased ICF Ca ____MLCK phosphorylates (and activates) myosin heads ____MLCP dephosphorylates (and inactivates) myosin heads ____Activated myosin heads causes smooth muscle contraction A. 7,5,6,2,4,1,3 B. 2,3,4,7,6,5,1 C. 2,7,3,1,4,6,5 D. 2,5,6,1,3,4,7 Arranged according to the sequence of Action Potential. A. A stimulus from a sensory cell or another neuron causes the target cell to depolarize toward the threshold potential. B. The membrane becomes hyperpolarized as K+ ions continue to leave the cell. The hyperpolarized membrane is in a refractory period and cannot fire. C. The K+ channels close and the Na+/K+ transporter restores the resting potential. D. At the peak action potential, K+ channels open and K+ begins to leave the cell. At the same time, Na+ channels close. E. If the threshold of excitation is reached, all Na+ channels open and the membrane depolarizes. PREPARED AND EDITED BY: Lacasandile, D., Lajara, P., Lamsis, V., Laniog, T., Natividad, J., Navarro, A., Navalta, C., Inferitis, K.