Smooth Muscle
Author: Dr. T. Hoekman
Smooth muscle as a tissue is deceptively simple-appearing in its structure, but
the range of variations and details of its physiology is very complex. Smooth
muscle makes up the contractile portion of the "tubular" organs;
gastrointestinal tract, uro-genital tract, vasculature, and a wide variety of other
organs. Physically smooth muscle cells are much smaller than those of either
skeletal or cardiac muscle. They are spindle shaped, with a diameter of 2-5 um
and a length of 50-100 um. There are no visible striations when viewed under
the light microscope, although there is a fibrillar appearance to the myoplasm
which runs with the long axis of the cell. Biochemical analysis of smooth muscle
indicates the presence of the same primary molecular constituents as in cardiac
and skeletal muscle (e.g. actin and myosin) but without the highly organized
structural relationships seen in the other muscles.
Under high resolution eletronmicoscopy thick (13-17 nm diameter) and thin (58 nm diameter) filaments are seen and under some conditions "cross-bridgelike" lateral projections are seen on the thick filaments. It thus appears that
these "mini" thick filaments interact in a somewhat random fashion with actin
filaments running parallel to them in the myoplasm to produce tension and
shortening by a sliding filament mechanism analogous to that found in skeletal
and cardiac muscle. Because there are no sarcomeres, with their dimension
limits on the length-tension relationship, the range of lengths over which active
tension is possible is much greater than in striated muscle (will actively shorten
to 1/5 of lo and reversibly stretch to much greater lengths) . Scattered
throughout the cytoplasm and at certain regions of the sarcolemma are
aggregates of electron dense material known as dense bodies. Thin filaments
enter the dense bodies suggesting a role similar to Z-lines in striated muscle.
Two specialized types of cell-to-cell contacts are seen: nexus or gap junctions
are characterized by low electrical resistance connections between the adjacent
cells because small physical channels connecting them are present in the
structure. The function of the attacment plaque is more obscure but it appears
to be a more stable physical characteristic than nexuses which are very labile
(forming and disappearing in minutes or seconds). Filaments are often seen
terminating in these structures and it is postulated that they function as a
mechanical coupling from cell to cell for transmission of force.
The regulation of contractile activity has some similarities to striated muscle but
some important differences. Calcium appears to be the key trigger agent in
activating contractility, but the means by which it acts is novel. There is no
direct analogue to the T-tubules of striated muscle but there are "flask-shaped"
invaginations of the plasma membrane known as caveolae or which may
increase the surface area of external membrane interfacing the myoplasm for
calcium entry during excitation. Smooth muscle has greatly reduced
sarcoplasmic reticulum in comparison with striated muscle. There is a notable
juxtaposition of elements of the SR with the surface vesicles approaching within
10-20 nm. While the ability of the SR to accumulate Ca++ has been
demonstrated, it is not certain whether it can release the ion during excitation
as occurs in the other muscle types. While it is quite certain that contractility is
regulated by modulation of cytoplasmic Ca++ concentration the details of its
removal during relaxation are not well understood at the present time. Most
smooth muscle ceases to contract within a few seconds after introduction of
calcium-free extracellular fluid. This suggests that internal storage of activator
calcium in the SR is minimal.
The important qualitative difference in control of contractility in smooth muscle
exists at the level of the myofilaments. There is no direct equivalent to the
protein troponin found in the thin filaments of striated muscle. In fact the
regulation of actomyosin formation occurs at the myosin of the thick filament in
a very different fashion from that described earlier. The sequence of events and
the principal characters are as follows:
1. Calcium concentration in the cell increases due to increased conductance
of the sarcolemma.
2. Ca++ binds with a cytoplasmic protein, calmodulin which has many
structural similarities to troponin.
3. Calmodulin*Ca++ complex binds to and activates a myosin kinase which
catalyzes the phosphorylation of a portion of the globular head of the
myosin (utilizes cyclic AMP).
4. The myosin is now activated and can form actomyosin complexes and
produce force and shortening in the usual fashion.
5. When Ca++ concentrations drop, calmodulin-Ca++ dissociates from the
myosin kinase, and a second cytoplasmic enzyme dominates the
situation.
6. This Phosphatase dephosphorylates the myosin site and returns it to the
inactive state, resulting in relaxation.
There are three general physiological characteristics that apply across all
categories of smooth muscle.
1. They are capable of slow sustained contractions maintained with a
minimum energy expenditure.
2. Motor innervation is exclusively via the autonomic nervous system.
3. They exhibit a degree of intrinsic tone (A basal level of active resting
tension upon which contractions or relaxations are superimposed.
Based upon differences in their physiology two broad categories of
smooth muscle can be distinguished; Unitary or visceral smooth
muscle and multi-unit smooth muscle.
Unitary smooth muscle is characterised by the presence of
spontaneous activity initiated in pacemaker areas with the muscle
(myogenic pacemaker activity). This activity spreads throughout the
muscle as if it were a single unit, hence the name unitary smooth
muscle. In this sense it is analogous to cardiac muscle in that it behaves
as a syncytium. The analogy is complete in that there are areas of
specialized cell-to-cell membrane contact nexuses which provide low
resistance pathways for excitation to spread from cell-to-cell. In addition
unitary muscle responds to stretch with an active contraction. Examples
of organs containing unitary smooth muscle are the G.I. tract, the
uterus, and the ureter.
Multi-unit smooth muscle does not contract spontaneously,
contraction must be initiated by neuronal activation through a
neuromuscular junction. The cells are activated in more than one region
by multiple motor nerves. Stretch does not produce an active contractile
response, and the cells are electrically independent. Small groups of cells
may be electrically coupled, but nexuses are very rare in this type of
smooth muscle. Coordinated contractile activity requires the action of
motor innervation. Examples of multi-unit muscle include ciliary and iris
muscles of the eye, and larger blood vessels.
While
this
classification system
is
useful
in
introducing
some
order
to
the
seeming chaos of
smooth
muscle
physiology,
many
smooth
muscles
overlap the two
categories.
For
example bladder smooth muscle develops tension in response to stretch,
but responds in a multi-unit fashion to nerve activity. It does not have a
myogenic pacemaker. In general the contractile response of smooth
muscle is coupled to a depolarization event, usually an action potential or
spike potential. However as compared to skeletal and cardiac muscle
there is an exagerated latency between the electrical and contractile
responses. This delay in contractile activation may be related to the
details of ultrastructure (Absence of a T-tubule system and a greatly
reduced SR) in relation to the striated muscle types. The surface vesicles
may be a focal site for calcium release and sequestration, and there is
evidence that the plasma membrane itself has unique calcium binding
characteristics. This calcium is then thought to be released by the
depolarization event and diffuses inward to trigger the contractile
response. With either mechanism the communication to the interior of
the cell occurs only by diffusion, hence the long latency for the response.
The membrane behaviour responsible for myogenic activity in unitary
smooth muscle has been described in detail for several specific muscles
and there are some differences in the details of the mechanism between
them. As a representative example I am using intestinal smooth muscle
(small intestine) as a model for this sort of activity. In intestinal smooth
muscle pacemaker potentials analogous in many ways to those in cardiac
muscle occur throughout the tissue. The main difference is the lack of a
specialized tissue site since all unitary smooth mucle cells have the
capacity for pacemaker function and the site of control is continually
shifting in response to local physiological conditions. The resting
membrane potential is much lower than in striated muscles, with values
from -30 to -70 mv. This is due to a relatively greater resting sodium
conductance and a much greater internal chloride concentration, so the
Goldman equation potential calculated from these values correlates with
the observed value.
In pacemaker cells and those near it which are electrically coupled by the
low-resistance nexuses there is a regular slow oscillation of the resting
membrane potential known as slow waves. If the peak of the slow wave
exceeds a critical potential level or threshold it results in the generation
of one or more action potentials. The action potential is propagated
throughout the electrically coupled smooth muscle cells and triggers a
tension response as shown in the figure below. The slow wave
depolarization cycle appears to based on cyclic activity of an electrogenic
sodium pump. It is highly dependent on metabolic activity and can be
blocked by agents which specifically block active pumping of sodium.
The action potential which is triggered by the slow wave results from a
transient increase in conductance for both sodium and calcium. If
sodium is removed from the extracellular fluid electrically stimulated
action potentials remain relatively unaltered if calcium concentrations are
maintained. Under these conditions the tension response is also intact,
pointing out the importance of calcium influx during the action potential
for activation of the contractile system. The contractile response
increases in relation to the positive amplitude of the slow wave. This is
related to longer period during which threshold is exceeded and the
generation of multiple action potentials and a proportional increase in
tension.
For intestinal smooth muscle this spontaneous pacemaker activity is
modulated by cholinergic and adrenergic neuronal imputs. Acetylcholine
results in a depolarization which shifts the slow wave upward to exceed
the threshold for a greater period of time during each cycle and
increasing the contractile response. Sympathetic activity has a
hyperpolarizing influence pulling the peak of the slow wave below
threshold and thus reducing electrical activity and tension generation.
Neither of the neurotransmitters appears to substantially alter the slow
wave itself but rather reset the baseline about which it oscillates. This
relation of excitation and inhibition to cholinergic and adrenergic
neurotransmission is not universal in smooth muscle. For example some
vascular smooth muscle responds to adrenergic stimulation with
excitation and to cholinergic stimulation with relaxation. These topics will
be considered in greater detail in the physiology and pharmacology of
the autonomic nervous system later in your training.
Topic #5 - Smooth Muscle
Readings
Silverthorn 2nd ed.
Silverthorn 1st ed.
p. 371 - 377
p. 348 - 356
Skeletal vs. Smooth Muscle
•
•
•
•
skeletal develops tension more rapidly; relaxes faster
smooth can sustain contraction longer without fatigue
o lower O2 consumption
smooth muscle tone =
difficulties in studying smooth muscle
o many types
o may be in layers running in different directions
o hard to stimulate directly
o acted on by many neurohormones
Smooth Muscle Cells
•
•
•
•
•
•
•
smaller than skeletal
actin/myosin arrangement
tropomyosin but no troponin
fewer myosin filaments but longer and covered with more heads
dense bodies =
slower ATPase action
not much sarcoplasmic reticulum
Types of smooth muscle
•
single unit (visceral)
o characteristics:
o example:
multi-unit
o
o
characteristics:
examples:
Molecular Events in Smooth Muscle Contraction
Contraction
•
•
•
caused by an increase in intracellular Ca+2
+2
o Ca enters from
calmodulin =
Ca+2/calmodulin activates MLCK (myosin light chain kinase)
o function:
Relaxation
•
•
•
calcium removed by
myosin light chain phosphatase prevents myosin activation
latch state =
maintains tension without using up ATP
other regulation:
o caldesmon =
o contraction occurs when caldesmon becomes
o
•
Regulation of Contraction
•
•
•
action potentials result from Ca+2 entering cell (not Na+)
some smooth muscle cells spontaneously depolarize
slow wave potentials =
•
•
pacemaker potentials
many smooth muscles have sympathetic and parasympathetic
innervation
blood vessels have ONLY
hormones and paracrine (locally acting) agents important
o histamine - causes
•
•
o
epinephrine - causes
nitric oxide causes
stretch alone is often enough to open Ca+2 channels
o
•
SMOOTH MUSCLE
Similarities to skeletal:
Actin
Myosin
Tropomyosin
Contractile mechanism
Display tetany and twitch summation.
Differences from skeletal:
1. Mononucleated
2. No striations.
3. No troponin.
4. Calmodulin mediated intracellular events.
5. No T-Tubules.
6. Poorly developed sarcoplasmic reticulum.
7. Action potentials carried by calcium ion
8. Very slow response.
9. Graded twitch strength (Some)
10. Display tone
11. Not every cell is innervated. (Some)
12. Display spontaneous activity. (Some)
13. Display excitation and inhibition. (Some)
14. Display plasticity (Stretch-Relaxation phenomenon). (Some)
15. Stretch causes a contraction (Some)
--------------------------------------------------------------------------------------1. Mononucleated.
Individual cells connected together via desmosomes, or sometimes gap
junctions. This affects how the cells can be stimulated (later).
2. Lack of striations in smooth muscle
Actin & myosin are not arranged in neat rows, but appear randomly
scattered.
Contractile mechanism the same - myosin cross-bridges attach to actin,
swing back, use ATP.
3. No Troponin
Excitation - contraction coupling different than in skeletal.
4. Calmodulin mediates intracellular events.
Calcium initiates contraction by binding to calmodulin.
Calcium-calmodulin binds to and activates myosin light chain kinase.
Myosin light-chain kinase then uses ATP to phosphorylate myosin heads
5. No T-Tubules
Slow Response
6. Poorly Developed Sarcoplasmic Reticulum
The calcium ion enters cell from extracellular fluid via voltage-gated
calcium channels. Pumped back out by active transport
7. Action potentials are carried by Calcium ion
Rather than Na ion causing depolarization, Ca++ enters via voltagegated Ca++ channels and is responsible for the depolarization. This
same calcium will then activate calmodulin.
Note: there may also exist messenger-gated calcium channels in the
same cells.
8. Very Slow Response
Everything is slow - voltage gated ion channels don't snap, they swing.
Action potential duration = 50 mSec.
Entry of calcium ion into cell, removal from cell.
Twitch latency - 200 mSec. Twitch duration - 1+ seconds
These because of lack of T-tubules and sarcoplasmic reticulum - it takes
time for calcium to spread throughout the cell and cause contraction.
Also Ca pump activity is sluggish. Thus once calcium is in, it takes longer
to remove it.
9. Graded twitch strength
Hormones and other substances may act as neuromodulators,
Hormones and other substances may act as open (or close) messengergated calcium channels.
Normally, a single AP will not make an excess of Ca++ available
intracellularly (contrast to skeletal muscle).
10. "Tone" in absence of nervous stimulation.
Not all calcium is removed from cytoplasm. In some cells, there is always at
least a little free cytosol Ca++, and thus always a small amount of active
calmodulin. This is one mechanism of tone.
11. Sometimes not every cell is innervated.
Some smooth muscles have every cell innervated. These are multi-unit smooth
muscles. In these instances, one cell may be contracting while another is not.
This allows a graded contraction, much like grading a skeletal muscle
contraction by firing fewer or more motor units.
In other muscles, not every cell receives its own innervation. In such instances,
there are two mechanisms of stimulation:
a. Diffusion of neurotransmitter
Each cell has neurotransmitter receptors.
b. Single Unit Smooth Muscle. Cell-to-cell transmission via gap junctions.
Entire muscle contracts as a single unit.
12. Display Spontaneous Activity (some)
Pacemaker potential due to decreasing permeability of membrane to K+
More K+ accumulates inside. Thus inside becomes more positive until threshold
is reached.
13. Excitation and Inhibition (some)
Excitatory neurotransmitters:
Open transmitter-gated calcium or sodium channels, to bring cell
to threshold.
Smooth muscle action potentials carried by Calcium ion, not
Sodium ion (i.e., voltage-gated channels are calcium channels).
Moreover, in some smooth muscle cells, the degree of opening of
the voltage-gated calcium channels is not all or none, but graded.
i.e., not on-off switch, but a dimmer control neuromodulators provide a mechanism for grading
of degree of contraction
Inhibition
Inhibitory transmitter opens K+ or Cl- channels, as in neurons.
14. Stretch - Relaxation Phenomenon. (Plasticity) (some)
The ability to change length without much change in tension.
Advantage: In bladder, intestine, etc.
15. Stretch produces contraction (Some)
Due to mechanical forces opening membrane calcium channels.