Smooth Muscle Cell Function and Microstructure (1/7/15)

What is stress-relaxation? What is the mechanism behind it?

Allows smooth muscle to change its length greatly without marked changes in tension. Tension is reduced or increased to its starting level when the muscle is stretched or shortened (rubber band analogy). This occurs because the loosely arranged actin and myosin filaments are able to rapidly remodel, allowing for sliding and bond rearrangement.

What is caldesmon? What is its function? How is it regulated?

Caldesmon binds to actin filaments at low [Ca2+], preventing myosin from binding actin and preventing contraction. At high [Ca2+] levels, Ca2+-calmodulin releases caldesmon from actin so myosin can interact with actin. Phosphorylation (via MAP kinase) of caldesmon reduces caldesmon binding to actin, so myosin can interact with actin.

How can you recognize a smooth muscle cell?

Centrally located nucleus with tapered ends (spindle-shaped). Smooth muscle cells closely packed, organized in bundles/sheets, and are enclosed in reticular fibers and basal lamina. When smooth muscle cells are contracted, the nucleus looks punctated (has points) -- this is how you can differentiate between dense CT and smooth muscle. When cut in cross-section, the cells have a variable look depending on where the section was cut.

What is electromechanical coupling?

Contraction with a change in membrane potential. Two forms: action potential dependent or a graded depolarization (stimulus causes depolarization and contraction without generation of an action potential).

What is a special feature of smooth muscle cells in the gut?

Inner layer of circular cells and an outer layer of longitudinal cells. When cut in cross-section, the circular cells look longitudinal and the longitudinal cells look circular.

How is smooth muscle involved in atherosclerosis?

Smooth muscle proliferation causes narrowing of the arteries.

What is tonus contraction? What is its importance?

The "resting" state of long-term steady contraction. Required in arterioles which must maintain tone for the lifetime of the individual, and in the SM of the gut and bladder wall.

How are thick and thin filaments arranged in smooth muscle?

The filaments are gathered into loose bundles attached to dense bodies (made of α-actinin) in the cytosol. The other end of the thin filaments are attached to attachment plaques located on the plasma membrane.

Describe the mechanism of calcium excitation contraction.

1. Ca2+ concentration increases due to a stimuli 2. Ca2+ binds calmodulin 3. Ca2+-calmodulin complex activates the myosin light chain kinase (MLCK) 4. MLCK phosphorylates and activates ATPase activity of the myosin head. 5. The myosin head can cleave ATP (allowing the myosin head to detach) and interact with actin as a molecular motor by "walking along" the actin molecule. As long as there is enough Ca2+ and ATP, myosin-actin cross-bridges can continue to cycle causing contraction.

What are the six ways that smooth muscle contraction/relaxation is regulated?

1. Intrinsic tone of smooth muscle (due to its molecular makeup) 2. Neuronal control: sympathetic nerves via adrenergic receptors. 3. Hormonal control: vasoconstricting (ex: angiotensin II) and vasorelaxing (ex: atrial natriuretic peptide) 4. Myogenic autoregulation: if smooth muscle is stretched, it will respond by constricting to maintain the lumen diamter and maintain constant blood flow 5. Metabolic substances: produced by surrounding tissue 6. Paracrine substances: produced by endothelial cells that diffuse locally

How is contraction terminated in smooth muscle?

1. Lowering [Ca2+] by sequestering it in the sarcoplasmic reticulum and through the Na+/Ca2+ exchanger. This inactivates the myosin light chain kinase, but does not stop smooth muscle contraction (myosin light chain is still phosphorylated). 2. The myosin light chain must therefore be dephosphorylated using the myosin light chain phosphatase (MLCP) -- this prevents attachment of myosin to actin.

What types of stimuli can cause smooth muscle to contract?

1. Mechanical impulses --> stretching causes depolarization and influx of Ca2+ --> contraction 2. Electrical depolarization (neural stimulation) 3. Chemical stimuli (hormones --> second messenger pathways)

How are myosin filaments organized in smooth muscle cells?

1. Myosin heads face only one direction on one side and on the opposite direction on the other side. 2. Staggered in parallel. 3. No central bare zone 4. Allows for thin filaments to be pulled over the entire length.

How does nitric oxide cause relaxation of arterial vascular smooth muscle?

1. NO is produced from arginine (once stimulated) in endothelial cells 2. NO diffuses into arterial smooth muscle cells 3. NO activates guanylate cyclase, converting GTP to cGMP 4. cGMP activates cGMP-dependent protein kinase, which can phosphorylate cellular proteins. Relaxation is caused by: decreasing intracellular Ca2+ and/or decreasing the Ca2+ sensitivity of proteins involved in the contractile system (ex: P-lation of MLCK reduces its activity and subsequently promotes relaxation/decreases contractility).

What are the differences in smooth and skeletal muscle contraction (5 things)?

1. Smooth muscle contracts in response to both neuromuscular synaptic transmission AND pharmaco-electrical coupling. 2. Smooth muscle cells can create and maintain tension for longer periods of time. 3. Smooth muscle requires less energy for contraction. 4. Velocity of smooth muscle contraction is much slower. 5. Smooth muscle can shorten more.

What are the functional differences in smooth and skeletal muscle cells?

1. Smooth muscle is not striated -- filaments are not arranged in sarcomeres, but loosely bundled with dense bodies. Sliding filament mechanism still occurs, however. 2. Cells are relaxed (20-500 μm long, 5-10 μm wide) 3. No t-tubules in smooth muscle. The SR is associated with caveolae (invaginations of the plasma membrane). 4. Smooth muscles do not have troponin, but have accessory proteins such as caldesmon, calponin, and calmodulin. 5. Smooth muscle cells may be connected by gap junctions.

What is pharmacomechanical coupling?

Contraction without a change in membrane potential. Usually caused by local tissue factors and hormones that can open calcium ion channels *without an action potential* (especially since Ca2+ release activates K+ channels, causing hyperpolarization).

What properties of smooth muscle account for its slow, steady contractile response?

Cytosolic Ca2+ levels rise and fall much more slowly than in skeletal muscle. Actinomyosin network is more disordered and does not operate under the tropomyosin-troponin system (so muscle is not as rapidly turned on and off).

Where does the Ca2+ for smooth muscle contraction mainly derive? How can calcium ions enter the cytosol?

Cytosolic [Ca2+] is mainly influenced by the Ca2+ that enters the cell via plasma-membrane Ca2+ channels. Ca2+ can enter the cytosol through voltage-independent channels (receptor-ligand interactions), from the sarcoplasmic reticulum (via IP3 initiation), and through voltage-gated channels (AP).

What is the importance of the latch state?

In the latch state, MLCP dephosphorylates MLC (turning off ATPase) while the myosin is still attached to actin (ATP cannot be cleaved, so myosin cannot detach). The myosin cross bridge remains attached to actin for a long time without consuming additional ATP.

Where is smooth muscle located?

In the viscera, the vascular system, in arrector pili muscle in the skin, and in intrinsic muscles of the eye.

What is the difference between multi-unit and single-unit smooth muscle? What are examples of both?

Multiunit smooth muscle cells are composed of discrete, independently innervated fibers (act as separate motor units). Found in the ciliary muscle of the eye. Single-unit smooth muscles are ionically coupled by gap junctions and allow for contraction of a single large area at once (act as one motor unit). Typically found in the walls of the gut and in arteries.

What is the importance of myoepithelial cells and oxytocin in lactation?

Myoepithelial cell stimulation by oxytocin is required for secretion of milk.

What specialized cell is found during fibrosis?

Myofibroblasts (considered specialized smooth muscle cells and/or specialized fibroblasts). Seen in liver cirrhosis and lung fibrosis (from too much smoking).

How is smooth muscle involved in asthma attacks or allergic reactions?

Smooth muscle of the bronchi contract and the airways narrow. Can be treated by using drugs (inhalants) that relax smooth muscle.

What is the difference in adult cell potential between skeletal, cardiac, and smooth muscle cells?

Skeletal and cardiac cells only perform hypertrophy, while smooth muscle cells perform hypertrophy and hyperplasia.

Describe an action potential in smooth muscle cells. What are the different types of action potentials that occur in smooth muscle cells?

Slower rate of rise because more dependent on Ca2+ concentration, and Ca2+ channels open more slowly. Three different forms of action potentials: 1. Simple spike 2. Plateau 3. A series of slow waves

How can smooth muscle contractile force be modulated (calcium-sensitization)?

The level of intracellular Ca2+ directly effects the balance of phosphorylation and dephosphorylation of the myosin light chain (via how much MLCK is activated). Changing the balance of MLCP and MLCK can change the force of contraction: 1. By inhibiting MLCP, the same amount of calcium can generate more force (less MLCP vs. MLCK -- more myosin heads are phosphorylated and active) and increase contractility. 2. Conversely MLCK can be phosphorylated to decrease efficiency, decreasing the sensitivity to calcium and dampening contractility.