Location, Functions, and Contraction Patterns of Smooth Muscle

General characteristics of smooth muscle

• Nonstriated muscle (i.e., no striations on microscopy)
• Involuntary muscles that generally control internal organs and vessels
• Innervated by the ANS

Locations

Smooth muscle is primarily found in the walls of hollow structures and some visceral organs, including:

• Vasculature 
• GI tract: 
  • Esophagus Esophagus The esophagus is a muscular tube-shaped organ of around 25 centimeters in length that connects the pharynx to the stomach. The organ extends from approximately the 6th cervical vertebra to the 11th thoracic vertebra and can be divided grossly into 3 parts: the cervical part, the thoracic part, and the abdominal part. Esophagus
  • Stomach
  • Small and large intestines
  • Rectum Rectum The rectum and anal canal are the most terminal parts of the lower GI tract/large intestine that form a functional unit and control defecation. Fecal continence is maintained by several important anatomic structures including rectal folds, anal valves, the sling-like puborectalis muscle, and internal and external anal sphincters. Rectum and Anal Canal
  • Sphincters
• Respiratory tract: 
  • Trachea Trachea The trachea is a tubular structure that forms part of the lower respiratory tract. The trachea is continuous superiorly with the larynx and inferiorly becomes the bronchial tree within the lungs. The trachea consists of a support frame of semicircular, or C-shaped, rings made out of hyaline cartilage and reinforced by collagenous connective tissue. Trachea
  • Bronchi and bronchioles
• Female reproductive tract: 
  • Uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall
  • Fallopian tubes Fallopian tubes The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The fallopian tubes receive an ovum after ovulation and help move it and/or a fertilized embryo toward the uterus via ciliated cells lining the tubes and peristaltic movements of its smooth muscle. Posterior Abdominal Wall
  • Vagina
• Urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract: 
  • Ureters
  • Urinary bladder
  • Urethra
• Iris of the eye
• Piloerector muscles in hair follicles

Functions

• Control the diameter of hollow structures or openings (e.g., blood vessels, airways, sphincters, pupils)
• Cause movement through hollow structures (e.g., GI tract, fallopian tubes)
• Expulsion (e.g., urine from the bladder, fetus from the uterus)

Patterns of contraction, relaxation, and resting states

Based on function, smooth muscle from different tissues will be in different states of contraction at rest.

• Normally contracted: 
  • Muscles that are normally contracted, and relax when stimulated
  • Example: sphincters
• Normally relaxed:
  • Muscles that are normally relaxed, and contract when stimulated
  • Examples: bladder, uterus
• Normally partially contracted (muscle with resting tone):
  • Muscles that are in states of partial contraction, with the ability to contract or relax further depending on the stimulus
  • Examples: blood vessels, airways
• Normally active muscles:
  • Muscles in fairly constant motion
  • Example: smooth muscles in the GI tract

Types of Smooth Muscle

There are 2 primary types of smooth muscle tissue: single- and multi-unit types.

Sing-unit type

Sing-unit type smooth muscles are also called phasic units:

• Myocytes are electrically coupled to one another via gap junctions: 
  • Transmit impulses to adjacent myocytes → produces a functional syncytium (a large number of cells contracting as a single unit)
  • Allows slow, wavelike contraction
• Found in blood vessels and most visceral organs, including those in the digestive, respiratory, urinary, and reproductive tracts
• More common than the multi-unit type
• Often forms multiple layers (e.g., circular and longitudinal layers in the GI tract)

Multi-unit type

Multi-unit type smooth muscles are also called tonic units:

• Individual cells are separated by a basement membrane.
• Lack gap junctions
• Each cell is innervated by its own nerve fiber → cells contract independently from one another
• Found in: 
  • Largest arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries and pulmonary passages
  • Piloerector muscles of hair follicles
  • Iris of the eye

Stimulation of Smooth Muscle Cells

Possible stimuli

In skeletal muscle, the stimulus for a muscle fiber to contract always comes via a motor neuron. Smooth muscle, however, may be stimulated in a variety of ways.

• Stimulation via the ANS
  • Acetylcholine
  • Norepinephrine (NE)
• Coupling with other smooth muscle cells via gap junctions 
• Intrinsic pacemaker ability: certain cells in the GI tract
• Hormones:
  • Circulating epinephrine/NE (released by the adrenal medulla)
  • Oxytocin
  • Histamine
• Metabolic factors:
  • CO₂ levels
  • O₂ levels
  • pH levels
• Mechanical stretch

Diffuse junctions

For smooth muscle that is stimulated via the ANS, the neurotransmitters are released from the nerves at diffuse junctions (rather than at a neuromuscular junction (NMJ) found in skeletal muscle).

• Varicosities: beadlike swellings along the length of the autonomic nerve fiber containing synaptic vesicles with neurotransmitters
• The nerve fibers pass over and run between multiple different myocytes.
• Neurotransmitters are released from the varicosities → stimulate receptors, which are located all over the surface of the muscle cell
• Diffuse junction: 
  • Describes the junction between a varicosity and receptors on the smooth muscle cell surface
  • A single nerve fiber may have multiple different diffuse junctions, with multiple different smooth muscle cells

Excitation–Contraction Coupling in Smooth Muscle

Like skeletal muscle, smooth muscle requires an influx of Ca²⁺ into the sarcoplasm in order to initiate a contraction. Smooth muscle, however, uses different processes to achieve this influx of Ca²⁺: Ca-induced Ca release (CICR) and ligand-mediated Ca release.

Calcium-induced calcium release

Channels involved:

• CICR channels:
  • Located on the sarcoplasmic reticulum (SR) with the muscle cell
  • When open, CICR channels allow Ca²⁺ efflux from the SR into the sarcoplasm.
  • Stimulated to open by Ca²⁺ (on the sarcoplasm side)
• L-type Ca channels:
  • Voltage-gated, membrane-bound Ca channels
  • Located in small invaginations in the sarcolemma called caveolae
  • Located in close proximity to the CICR channels on the SR

Process of CICR:

• A stimulus changes the membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential of the sarcolemma.
• This opens the L-type Ca channels.
• Small amounts of Ca²⁺ enter the cell.
• This Ca²⁺ triggers CICR channels on the SR to open.
• There is a large Ca²⁺ efflux from the SR.
• Ca²⁺ causes actin–myosin binding.

Ligand-mediated calcium release

• A stimulus activates a membrane-bound protein.
• The membrane-bound protein generates an intracellular 2nd messenger.
• The 2nd messenger stimulates a ligand-gated channel on the SR to open → Ca²⁺ efflux
• Common example:
  • Stimulus activates a G-protein-coupled receptor (GPCR)
  • GPCR activates phospholipase C (PLC).
  • PLC cleaves phosphatidylinositol-4,5-bisphosphate (PIP₂) to produce:
    • Inositol trisphosphate (IP₃): functions as the 2nd messenger in this case
    • Diacylglycerol (DAG)
  • IP₃ binds an IP₃-gated channel on the SR → channel opens, allowing Ca²⁺ efflux

How intracellular Ca leads to actin-myosin interaction in smooth muscle

Striated muscle is regulated via changes in actin-regulatory proteins, whereas smooth muscle is regulated via phosphorylation of myosin.

• In skeletal muscle: 
  • The troponin–tropomyosin complex covers the myosin-binding sites on actin, preventing actin-myosin interaction.
  • Ca causes a conformational change in the troponin–tropomyosin complex.
  • This conformational change reveals the myosin-binding sites on actin → actin and myosin can interact 
  • An ATP binds the myosin head and crossbridge cycling can begin (which leads to muscle contraction).
• In smooth muscle: 
  • Intracellular Ca²⁺ in the sarcoplasm binds calmodulin.
  • Calmodulin is an enzyme that activates myosin light chain kinase (MLCK).
  • MCLK transfers a phosphate from ATP to myosin.
  • Phosphorylated myosin activates myosin ATPase within the myosin.
  • Myosin can now interact with actin.
  • An additional ATP binds the myosin head and crossbridge cycling can begin (leading to muscle contraction).
• Myosin phosphatase:
  • Inhibits myosin by cleaving off the phosphate required for myosin activation in smooth muscle
  • Myosin phosphatase inhibitors help to activate myosin (because the inhibitor is inhibited), and include:
    • Protein kinase (PK) C
    • Rho-kinase
• Graded contractions based on amount of sarcoplasmic Ca:
  • More Ca = stronger contractions
  • Less Ca = weaker contractions

Contraction and Relaxation of Smooth Muscle Tissue

Actin and myosin arrangement in smooth muscle

Unlike in skeletal muscle, actin and myosin are not arranged in sarcomeres in smooth muscle. In smooth muscle:

• Actin is attached to protein masses called dense bodies, which are:
  • Attached to (and technically part of) the cytoskeleton Cytoskeleton A cell's cytosol is the liquid inside the cell membrane that surrounds the organelles and cytoskeleton. The cytosol is a complex solution where many biochemical processes take place. The Cell: Cytosol and Cytoskeleton
  • Scattered throughout the sarcoplasm and on the inner face of the sarcolemma (muscle cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane)
  • Connected to one another via intermediate filaments
• No Z lines connecting the actin
• Myosin is located between the actin.
• Myosin pulls on actin → actin pulls on dense bodies → dense bodies move closer to one another → entire muscle cell scrunches together = contraction

Crossbridge cycling in smooth muscle

Also known as the sliding filament theory of muscle contraction, crossbridge cycling is the process by which the myosin and actin move along each other, shortening the muscle cell and causing muscle contraction. In smooth muscle, myosin must be phosphorylated by MLCK in order for crossbridge cycling to begin.

Process:

• ATP binds the myosin head.
• Myosin ATPase hydrolyzes the ATP → ADP:
  • Moves the myosin head into a high-energy “cocked” position
  • This movement is known as the recovery stroke.
• The cocked myosin head binds a myosin-binding site on actin, forming a crossbridge
• Power stroke: 
  • Myosin releases the ADP and phosphate.
  • Myosin head expels the energy → returns to the flexed position, pulling the thin filament with it 
  • Since many myosin heads are bound simultaneously, the actin remains in its new position rather than “slipping back” to its original position.
• Myosin binds a new ATP, causing it to release from the actin.
• The cycle starts over.

Relaxation

Relaxation occurs when Ca²⁺ is removed from the sarcoplasm.

• Ca²⁺ is removed from the sarcoplasm via 2 mechanisms:
  • Move the Ca²⁺ out of the cell via surface proteins:
    • Ca²⁺ ATPase 
    • Na⁺-Ca²⁺ exchanger
  • Sequester Ca²⁺ in the SR via sarco-/endoplasmic reticulum Ca-ATPase ( SERCA SERCA Calcium-transporting ATPases that catalyze the active transport of calcium into the sarcoplasmic reticulum vesicles from the cytoplasm. They are primarily found in muscle cells and play a role in the relaxation of muscles. Skeletal Muscle Contraction) pumps
• Without Ca²⁺, myosin is dephosphorylated by myosin phosphatase → inactivated myosin is no longer able to execute power strokes

Latch-bridge state

• A state in which myosin is dephosphorylated (can no longer crossbridge cycle) but remains attached to actin = maintains some tension
• Allows the muscle to maintain tone without expending much energy
• Example: in sphincters, which maintain contraction as their “resting” state

Response to stretch

Stretch may trigger either contraction or the stress-relaxation response in some smooth muscle tissue.

• Stretch leading to contraction:
  • Some tissue contains mechanically gated Ca²⁺ channels in the sarcolemma
  • This results in an ↑ in intracellular Ca²⁺ with stretch → leads to contraction
  • Examples: stretch in the esophagus or colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix trigger peristalsis contractions
• Stress-relaxation response:
  • Some tissues will contract and resist stretch briefly before relaxing in response to stretch.
  • Example: urinary bladder

Differences Between Smooth Muscle and Skeletal Muscle Contraction