Smooth Muscle Physiology
What does a reduction in myoplasmic cAMP lead to?
Activation of myosin kinase and less phosphorylation of PKA. Activated myosin kinase phosphorylates myosin of smooth muscle thick filaments, leading to contraction. The arterioles will vasoconstrict.
What is the range of length in which smooth muscle can still exert tension?
From 1/2 of its resting length to 2.5x its resting length. This is a 5x variation.
What types of gastric hormones influence smooth muscle contraction?
Gastrin Cholecystokinin Secretin Motilin Neurotensin
What is the mechanical design of smooth muscle generally specialized for?
Generally, smooth muscle was designed to be slow, but NOT weak, and economical. It is highly specialized for its role in the body.
What hormones influence smooth muscle contraction?
Histamine Serotonin Vasopressin Oxytocin Angiotensin Substance P Gastric hormones
Why is the ability of smooth muscle to develop tension over a wide range important?
Hollow organs, which are lined with smooth muscle, can vary in diameter a great amount (i.e. the bladder). Smooth muscle must remain able to generate active tension over the entire usual range of muscle fiber lengths.
What are other factors that are not autonomic neurotransmitters that can modify contractile activity?
Hormones Mechanical stretch Local metabolites Drugs Ca2+ antagonists K+ channel openers Nitric oxide/cGMP stimulators
How is Ca2+ released from SR of smooth muscle?
It can be Ca2+ induced Ca2+ relase or via IP₃, with elevated levels due to the activation of G-protein coupled receptors.
What does PLC do?
It catalyzes the hydrolysis of PIP2 to IP3 and DAG.
What happens to the IP3?
It diffuses within the cell to the ER and SR and causes Ca2+ release. In smooth muscle, IP3 binds to a channel in the SR membrane, IP3R, that is a member of the same superfamily as ryanodine receptor (the SR Ca2+ release channel).
How is single-unit smooth muscle stimulated?
It does not require nervous system stimulation to contract. It is self excitable, with groups of fibers within single unit smooth muscle producing spontaneous activity. Activity may often be modulated by the autonomic nervous system and other factors.
What effect does α2 adrenergic receptors have?
It has the opposite effect of β₂ adrenergic receptors.
In comparison to skeletal muscle, how much tension per unit of cross sectional area can smooth muscle generate?
It is comparable, or more.
What type of channel is IP3R?
It is related to ryanodine receptors. It is a ligand gated channel and opens when it binds to IP3.
What happens when IP3R opens?
It releases Ca2+ from the SR, causing the smooth muscle to contract.
What causes the spontaneous depolarization of pacemaker activity?
It results from the activation of a small cationic current (mostly Na+)
What is the 4th method of generating a smooth muscle contraction?
Pharmacomechanical coupling in which changes of tension development are caused by drugs or hormones. Sometimes this can occur in the absence of significant changes in membrane potential.
What kind of coupling is β₂ adrenergic receptors an example of?
Pharmacomechanical coupling, because it does not need to change the membrane potential to work.
What happens when intracellular Ca2+ is increased?
Phosphorylation of myosin by: 1. Ca2+ binds to the calmodulin within the smooth muscle fiber 2. Ca2+-calmodulin complex binds to and activates *myosin kinase* (myosin light chain-kinase, *MLCK*) 3. The activated myosin kinase then phosphorylates myosin.
How much thin actin filament does smooth muscle contain?
Relative to striated muscle, thin filaments are more numerous in smooth muscle - about 10 thin filaments per thick filament, vs 2 sets of thin filaments per thick filament in striated muscle. The thin filaments of smooth muscle are also *longer than those of striated muscle*.
How does smooth muscle relax?
Relaxation of smooth muscle happens when Ca2+ is moved back into extracelluluar fluid across the surface membrane and by active pumping of Ca2+ back into SR
What is the basic structure/shape of smooth muscle?
Smooth muscles are spindle shaped and are much smaller than skeletal muscles. They are about 2-10 microns in diameter and about 50-400 microns long.
What is the 2nd method of generating a smooth muscle contraction?
Spontaneous potential changes can trigger action potentials, leading to contraction. Slow wave activity is associated with action potentials.
What is the overall result of β₂ adrenergic receptors in arteriolar smooth muscle?
The activation of β₂ adrenergic receptors in arteriolar smooth muscle causes the muscle to relax, leading to vasodilation.
How distinct is the difference between single and multi-unit smooth muscle?
The distinction is not great, with the categories an "over-simplification". It is difficult to separate in some tissues.
What is the role of innervation of smooth muscle?
The innervation does not normally initiate contraction, but it can modify both the rate of activity and the strength of contraction.
What parts of the nervous system typically innervates smooth muscle?
Typically from symathetic and parasympathetic branches of the autonomic nervous system.
What local metabolites have effects on smooth muscle contraction?
CO2 lactic acid ADP
What are the 3 functional roles of smooth muscle contraction?
*Maintains pressure* against the contents within a hollow organ or tube. *Propels contents* through a hollow organ or tube *regulates internal flow* of contents by changing tube diameter (resistance)
What are dense bodies?
Dense bodies are structures in smooth muscle. They are equivalent to Z-lines in striated muscle in that they anchor the thin filaments. Dense bodies contain many of the same proteins found in Z lines of striated muscle.
What is the consequence of relatively few gap junctions?
A small number of neighboring cells act as a unit. The multiple discrete units act independently and must be separately stimulated by nerves to contract.
What is the general resting potential of smooth muscles?
Around -50 to -70mV
What factors can modify contractile activity of smooth muscle?
Autonomic neurotransmitters: - β₂ adrenergic receptors - α₂ adrenergic receptors -α₁ adrenergic receptors couple to phospholipase C (PLC) via G-proteins.
How are smooth muscles categorized? What are the two categories?
Based on their electrical coupling between fibers. Single-unit smooth muscle Multi-unit smooth muscle
Why is there no meaningful or unique length-tension or force-velocity relationship for some types of smooth muscles in their physiological location within the body?
Because smooth muscle is so highly dependent on external influences.
How do the other factors work on contraction of both single unit and multi unit smooth muscle?
By changing permeability to Ca2+ of the surface membrane and/or the SR.
What led to the past conclusion that smooth muscle was poorly developed skeletal and cardiac muscle?
Due to the lack of striations observed in light and electron micrographs. Current imaging of its contractile apparatus remains not well understood.
How quick is diffusion of Ca2+ in smooth muscle cells?
Due to the small diameter of smooth muscle cells, diffusion from the surface to the center of the fiber is a relatively fast process.
What are dense areas?
Essentially dense bodies that are associated with sarcolemma and are involved in mechanical coupling between neighboring cells.
What role does Ca2+ have in smooth muscle?
Even though thin filaments of smooth muscle do noth contain troponin and tropomyosin, increased intracellular Ca2+ will turn on contraction in smooth muscle. The mechanism is very different from skeletal/cardiac muscle.
T/F: All types of single-unit smooth muscles are self-excitable.
False. Many, but not all, types of single-unit smooth muscle are self-excitable. Groups of specialized smooth muscle cells in this tissue generate spontaneous electrical activity that can spread to other cells via gap junctions.
How is the length-tension relationship for smooth muscle compared to skeletal/cardiac muscle?
In a limited sense, they are qualitatively similar. There is a relatively broad range of lengths where tension development is at or near its maximum. At both shorter and longer lengths, active tension declines.
Where are β₂ adrenergic receptors primarily found?
In arteriolar smooth muscle of vessels of coronary circulation and skeletal muscle.
What is the typical arrangement of smooth muscle cells?
In sheets
Where is smooth muscle found?
In the walls of hollow internal organs: All blood vessels except capillaries Gastrointestinal tract Urinary bladder
How do β₂ adrenergic receptors work?
Like all other adrenergic and muscarinic receptors, they work via G-proteins. For β receptors, the activated G-proteins activate adenylyl cyclase that catalyzes the conversion of ATP to cAMP, resulting in elevated intracellular cAMP levels. The increased cAMP activates protein kinase A (PKA).
What role does Ca2+ concentration have with smooth muscles?
Like striated muscle, increased myoplasmic Ca2+ is an important trigger for contraction in smooth muscle cells.
How are smooth muscles joined to each other?
Mechanically coupled, with varying degrees of electrical coupling.
What causes pacemaker activity?
Membrane potential gradually and spontaneously changing because of shifting patterns of membrane permeability. It is very similar to pacemaker activity in the heart.
How does Ca2+ enter the cell?
Most of the Ca2+ enters from the extracellular fluid across the cell membrane via: Voltage gated Ca2+ channels Ligand gated Ca2+ channels Receptor Gated Ca2+ channels Stretch-activated Ca2+ channels Some Ca2+ is also released from the SR, but SR in smooth muscle is relatively poorly developed.
How quickly does smooth muscle contract/relax?
Much more slowly than skeletal muscle, with single contractions lasting as long as several seconds.
How are multi-unit smooth muscle cells junctioned?
Multi-unit smooth muscle contains relatively few gap junctions. Therefore a small number of neighboring cells act as one unit.
Where are multi-unit smooth muscles found?
Multi-unit smooth muscle is found in: Walls of larger blood vessels Iris of the eye Airways of the lungs Skin surrounding hair follicles
What are tonic smooth muscles?
Muscles that are partially active all the time. They are found in walls of most blood vessels Airways of the lungs Various sphincters, all of which maintain a continuous level of partial contraction that is called *tone*
What are phasic smooth muscles?
Muscles that do not maintain resting tone, but instead contract rhythmically or intermittently. They are found in the GI Reproductive and uninary systems
Why does smooth muscle contract/relax slower?
Myosin ATPase of smooth muscle splits ATP at a much slower rate than in skeletal muscle, resulting in slower cross-bridge cycling.
What is the reason why increased cytoplasmic cAMP decreases smooth muscle contraction but increases contraction of the heart?
Myosin light chain kinase, MLCK. In smooth muscle, elevated cAMP leads to activation of PKA, which leads to phosphorylation of myosin light chain kinase, which inactivates this kinase and thereby reduces the phosphorylation of myosin, leading to relaxation. In the heart, elevated cAMP causes the phosphorylation and activation of PKA, leading to the facilitation of several channel types, as well as the Ca2+ pump, with the result of increased force of contraction.
Are action potentials always needed to generate contraction of smooth muscle cells?
No
Do all smooth muscles generate action potentials?
No, not all smooth muscle cells generate action potentials.
Does smooth muscle have a transverse tubular system?
No, they do not. They have a sarcoplasmic reticulum, but it is much more poorly developed than in skeletal or cardiac muscle.
Does the α2 adrenergic receptors use membrane potentials?
No, this is also a pharmacomechanical coupling example. It also doesn't require change in Ca2+ concentration.
Do tonic smooth muscles produce an action potential?
No, tonic muscles are not associated with action potentials. It is affected by membrane potentials. The resting tone of tonic smooth muscle is not dependent on elevated myoplasmic Ca2+ concentration.
Does thin actin filaments use troponin and tropomyosin?
No, unlike skeletal and cardiac muscle filaments, smooth muscles do not contain troponin and tropomyosin. They use proteins called calponin and caldesmon that may serve regulatory roles.
Does α1 adrenergic receptors require a change in membrane potential?
No. It is another example of pharmacomechanical coupling
How does the ANS synapse with single unit smooth muscle cells?
Not in the typical NMJ fashion of skeletal muscle. Adrenergic and cholinergic receptors are dispersed over the entire surface of the smooth muscle cells. The post ganglionic autonomic fibers travel across the surface of smooth muscle cells. Varicosities in the axon terminal release transmitters that diffuses to receptor sites on the muscle cells.
When can myosin of thick filament bind to actin?
Only when the myosin regulatory light chain is phosphorylated.
What does PKA do in arteriolar smooth muscle?
PKA phosphorylates and inactivates myosin kinase (myosin light chain kinase). Inactivated myosin kinase cannot phosphorylate myosin of the thick filaments of smooth muscle. Since only phosphorylated myosin of the thick filaments can bind to actin of the thin filmaments, the inactive myosin kinase cannot phosphorylate the thick chain, and the muscle cannot contract.
What are the most common types of spontaneous depolarizations?
Pacemaker activity Slow-wave potentials
Describe single-unit smooth muscle. What kind of junctions bind single-unit smooth muscle?
Single-unit smooth muscle is the most common type. The units are electrically coupled via gap junctions, which allow excitation and contraction as a single unit.
How does smooth muscle's operation range compare to skeletal muscle's?
Skeletal is 70-130% Smooth is 50%-250%
Which of the following muscle cell types extend the entire length of the whole muscle? Skeletal Smooth Cardiac
Skeletal muscle cells extends the entire length of the muscle Smooth muscle cells do not extend the entire length of the muscle Cardiac muscle cells do not extend the entire length of the muscle.
What is the 3rd method of generating a smooth muscle contraction?
Slow oscillations in potential (sometimes reflecting changes in the activity of electrogenic pumps) can cause changes in tonic contractile activity in the absence of action potentials.
What kind of ionic channels does smooth muscle have? What opens them?
Smooth muscle cells contain voltage-sensitive Ca2+ channels, opened by membrane depolarization. Some smooth muscle cells contain receptor activated Ca2+ channels, which require binding of specific substances for receptors to open.
What happens after myosin is phosphorylated?
The phosphorylated myosin of smooth muscle thick filaments binds to actin of the thin filaments allowing cross bridge cycling and contraction. This process is much slower in comparison to skeletal/cardiac muscle.
What is the relative size of thick myosin filaments, compared to skeletal muscle?
The thick myosin filaments found in smooth muscle are longer than the ones found in skeletal muscle.
What do Ca2+ antagonist do to influence smooth muscle contraction?
These drugs block voltage dependent Ca2+ channels, reducing Ca2+ influx and Ca2+ induced Ca2+ relase. Examples include: nifedipine Verapamil Diltiazem
What do K+ channel opener drugs do to influence smooth muscle contractions?
These drugs cause hyperpolarization of smooth muscle cells, which decreases Ca2+ influx through voltage dependent Ca2+ channels and promotes relaxation of smooth muscle and vasodilation of peripheral blood vessels. Example: pinacidil
What do drugs do to influence smooth muscle contraction?
They affect excitation-contraction coupling or other contractile mechanisms in vascular smooth muscle cells. These drugs can be used to treat hypertension.
How are the filaments arranged in smooth muscle?
They are not arranged into sacromeres and smooth muscle does not contain myofibrils. The thick and thin filaments are organized somewhat diagonally, with a basic form of elongated diamond shaped lattice.
What are intermediate filaments of smooth muscle?
They are not contractile elements. Instead, they are part of the cell's *cytoskeleton* and are *probably responsible for some of the elastic properties of smooth muscle.*
What do α1 adrenergic receptors do?
They couple to phospholipase C (PLC) via G proteins.
What influence does nitric oxide/cGMP stimulators have on smooth muscle contraction?
They elevate cGMP concentrations in the cytosol. cGMP relaxes smooth muscle. One source are NO donors such as nitroglycerin.
What excites a phasic smooth muscle, and what does this cause?
They usually produce action potentials that either initiate contraction or increase the contractile response.
How do α2 adrenergic receptors work?
They work via G-protein with an inhibitory α subunit causing inhibition of adenylyl cyclase, which results in decrease in myoplasmic levels of cAMP.
What are the 3 types of filaments in smooth muscles?
Thick myosin filaments Thin actin filaments Intermediate filaments
What is the 1st (these numbers mean nothing, just random from the list!) method of generating a smooth muscle contraction?
Triggered action potentials open voltage-sensitive Ca2+ channels in the cell membrane to generate slow summating tension.
T/F: Mechanical stretch has an influence on smooth muscle contraction
True
T/F: Smooth muscle is not striated and is not subject to voluntary control
True
What smooth muscle group is only innervated by sympathetic innervation?
Vascular smooth muscle
What is another name for single-unit smooth muscle?
Visceral smooth muscles due to it being usually found in visceral organs, such as walls of GI tract, reproductive and urinary tracts, and smooth muscle of small blood vessels.
What is another useful categorization of smooth muscle? What are the categories?
Whether the smooth muscle cells in an organ/tissue are continuously active or only contract intermittently or rhythmically: - Tonic smooth muscles - Phasic smooth muscles
How are the thick myosin and thin actin filaments arranged in a smooth muscle cell?
While smooth muscles contain thick myosin and thin actin filaments, the contractile and cytoskeletal elements are not arranged transversely as they are in striated (cardiac and skeletal) muscle
Can smooth muscle cells maintain a low level of tone without electrical activity?
Yes, many smooth muscle cells, usually of single-unit type, can maintain a low level of tension (tone) even without electrical activity, and apparaently without elevated myoplasmic Ca2+ concentration.