MPP block 2 lecture 3.pdf

Where is smooth muscle found? All regions of the body, layered within the walls of blood vessels and airways How is striated muscle activated? by a handful of neurotransmitters and hormones How is smooth muscle activated? by hundreds of chemical signals How does smooth muscle affect organ volume?...

Where is smooth muscle found? All regions of the body, layered within the walls of blood vessels and airways How is striated muscle activated? by a handful of neurotransmitters and hormones How is smooth muscle activated? by hundreds of chemical signals How does smooth muscle affect organ volume? Plasticity of smooth muscle sarcomeres and cytoskeletal framework maintains contractility during changes in hollow organ luminal volume Minisarcomeres: densely packed actin and myosin filaments, organized into contractile units Thick Filaments: Two heavy chains (head and neck) Two pairs of light chains (essential and regulatory) myosin head: contains ATPase activity and an actin-binding site dense plaques: tethers arrays of muscle fibers to the sarcolemma, distributed over the entire cell surface and link adjacent cells mechanically Sarcoplasmic reticulum - tubular network that stores Ca2+ with release channels Activated by Ca2+ or (IP3) Sidepolar Model: myosin head groups within thick filament have a sided arrangement that allows two actin filaments to be pulled simultaneously in opposite directions What is the effect of the sidepolar model on myocytes? smooth muscle myocytes can shorten more than striated muscle fibers 1. Cellular Structure Smooth Muscle Cells (Myocytes): spindle-shaped (fusiform) with a single, central nucleus. smaller than skeletal muscle fibers, non-striated  Cytoskeleton: actin and myosin filaments, not arranged in sarcomeres, which accounts for the lack of striations. arranged randomly, enabling contraction in multiple directions. Dense Bodies: anchor actin filaments, scattered throughout the cytoplasm and attached to the cell membrane. function similarly to Z-discs in striated muscle, sites where force is transmitted during contraction. 2. Contractile Apparatus Thin Filaments: actin, along with regulatory proteins tropomyosin, caldesmon, and calponin. NO troponin Thick Filaments: myosin, interacts with actin filaments once it is phosphorylated, necessary for contraction. Myosin Light Chain Kinase (MLCK): enzyme activated by calcium-bound calmodulin, key role in the phosphorylation of myosin, triggering contraction. 3. Calcium Signaling Caveolae: Small invaginations in smooth muscle cell membranes that help concentrate ion channels, receptors, and signaling molecules. regulate calcium influx. Calcium Ions (Ca²⁺): enter the cell from the extracellular space through voltage-gated or ligand-gated calcium channels, or it can be released from intracellular stores in the sarcoplasmic reticulum. initiated contraction by binding calmodulin, activating MLCK and allowing myosin-actin interaction 4. Membrane system Sarcoplasmic reticulum: ○ Calcium-induced calcium-release channels - (CICR) opened by Ca2+ entering the myocyte via voltage-dependent Ca2+ channels ○ Inositol trisphosphate–gated calcium channels (IP3-gated Ca2+ channel) IP3 is a second messenger that communicates binding of chemical signals - hormones and neurotransmitters Myosin and Actin: ○ Skeletal Muscle: Myosin-actin interactions are organized into sarcomeres, and contraction is controlled by calcium binding to  troponin, allowing myosin to bind actin. This leads to rapid, forceful contractions. ○ Smooth Muscle: Myosin-actin interactions are randomly arranged (no sarcomeres). Contraction is regulated by phosphorylation of myosin through calmodulin-MLCK. Contraction is slower and more sustained. Membrane System: ○ Skeletal Muscle: Uses a well-developed sarcoplasmic reticulum (SR) and T-tubule system for fast calcium release and rapid contractions. ○ Smooth Muscle: Has a less developed SR, no T-tubules, and uses caveolae for calcium entry, leading to slower, sustained contractions. NMJ In Smooth Muscle: controlled by ANS, less developed than skeletal muscle Varicosities: sites of NMJ in ANS, series of varicosities along the length of an axon contact multiple smooth muscle cells Smooth Muscle Contraction: 1. Stimulus: The smooth muscle cell can be stimulated by various factors, including neurotransmitters (like norepinephrine), hormones (like oxytocin), and more! GPCR signaling activated by neurotransmitters and/or hormones, results in the activation of multiple signaling cascades involving: PLC and Rho-kinase PLC activation leads to the signaling of both IP3 and DAG IP3 binds the IP3 gated Ca²⁺ channel on the SR leading to an increase in intracellular calcium (see step "2" next) DAG activates PKC, activating CPI-17, leading to the inhibition of MLCP Rho-kinase activation leads to the inhibition of MLCP 2. Influx of Calcium: The stimulus leads to an influx of extracellular Ca²⁺ ions through voltage-dependent or receptor-operated calcium channels.  3. Calcium Binds to Calmodulin: The increased intracellular Ca²⁺ binds to the protein calmodulin, forming a Ca²⁺-calmodulin (Ca²⁺-CaM) complex. 4. Activation of MLCK: The Ca²⁺-calmodulin complex activates myosin light chain kinase (MLCK). Additionally, Ca²⁺-CaM inhibits the two actin bound myosin ATPase inhibitors (calponin and caldesmon). By inhibiting calponin and caldesmon it allows for the myosin head to experience appropriate ATP hydrolysis promoting cross bridge cycling. 5. Phosphorylation of Myosin: MLCK then phosphorylates the light chain of myosin molecules, enabling the myosin heads to interact with actin filaments. 6. Cross-Bridge Formation: The phosphorylated myosin heads bind to actin, forming cross-bridges. 7. Power Stroke: Using energy from ATP hydrolysis, the myosin heads undergo a conformational change, pulling the actin filaments inwards. This leads to muscle contraction. 8. Sustained Contraction: Smooth muscle can sustain contraction with little energy expenditure by latching the myosin heads onto actin, maintaining tension. Smooth Muscle Relaxation: 1. Removal of Stimulus: The initial stimulus (e.g., neurotransmitter or hormone) is removed or reduced. 2. Calcium Pump Activation: Active transport mechanisms, primarily SERCA pump, push Ca²⁺ ions out of the cell and back into the sarcoplasmic reticulum. 3. Decrease in Intracellular Calcium: As intracellular Ca²⁺ levels decrease, calcium unbinds from calmodulin. 4. Dephosphorylation of Myosin: Myosin phosphatase (MLCP) dephosphorylates the light chain of myosin, reducing its affinity for actin. 5. Cross-Bridge Detachment: As myosin is dephosphorylated, myosin-actin cross-bridges detach. 6. Muscle Relaxation: With fewer active cross-bridges, tension in the muscle decreases, leading to muscle relaxation. IBS: GI disorder associated with intestinal cramping, increased flatulence, and altered bowel habits, dysfunction of muscle contraction/relaxation IBS Treatment: options are limited, include antispasmodics Natural remedies: peppermint oil Act by blocking Ca2+ channels in the smooth muscle, reducing contractility and relaxing the muscle 5.Compare and contrast excitation-contraction coupling in smooth and skeletal muscle. excitation-contraction Coupling In smooth Muscles: multiple competing signals, all converge on Ca2+, myosin mediated (not actin like skeletal muscle) Three Calcium sources for contraction of SM: 1.Ca2+ influx across the sarcolemma 2.CICR from the SR 3. IP3-mediated Ca2+ release from the SR (downstream hormone/ligand mediated) 1. Ca²⁺ Influx Across the Sarcolemma: Voltage-Gated Calcium Channels (VGCCs): Depolarization of the smooth muscle membrane opens voltage-gated L-type calcium channels in the sarcolemma, allowing extracellular Ca²⁺ to flow into the cytoplasm. Receptor-operated Ca2+channels (ROCs): ROC-mediated Ca2+ fluxes are relatively minor, but do depolarize cells to aid in Ca2+ influx and contraction via L-type Ca2+ channels 2. Calcium-Induced Calcium Release (CICR) from the SR: The initial influx of Ca²⁺ from the extracellular space can trigger ryanodine receptors (RyR) on the sarcoplasmic reticulum (SR) membrane.  When activated by the presence of Ca²⁺, these receptors release additional calcium from the SR into the cytoplasm, amplifying the calcium signal and contributing to contraction. 3. IP3-Mediated Ca²⁺ Release from the SR: G-protein-coupled receptor (GPCR) activation leads to the production of inositol trisphosphate (IP3) via phospholipase C (PLC) activation. IP3 binds to IP3 receptors on the SR membrane, causing them to open and release calcium from the SR stores into the cytoplasm, which contributes to smooth muscle contraction. IP3-mediated Ca2+ release and smooth muscle contraction can occur independently of an action potential or other membrane potential change