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SMOOTH MUSCLE CONTRACTION AND
RELAXATION

R. Clinton Webb
Published Online: 01 DEC 2003 //
https://doi.org/10.1152/advan.00025.2003

 More  Sections  

Abstract

This brief review serves as a refresher on

smooth muscle physiology for those
educators who teach in medical and
graduate courses of physiology.
Additionally, those professionals who are in
need of an update on smooth muscle
physiology may find this review to be
useful. Smooth muscle lacks the striations
characteristic of cardiac and skeletal
muscle. Layers of smooth muscle cells line
the walls of various organs and tubes in the
body, and the contractile function of smooth
muscle is not under voluntary control.
Contractile activity in smooth muscle is
initiated by a Ca2+-calmodulin interaction to
stimulate phosphorylation of the light chain
of myosin. Ca2+ sensitization of the
contractile proteins is signaled by the
RhoA/Rho kinase pathway to inhibit the
dephosphorylation of the light chain by
myosin phosphatase, thereby maintaining
force generation. Removal of Ca2+ from the
cytosol and stimulation of myosin
phosphatase initiate the process of smooth
muscle relaxation.

Sheets or layers of smooth muscle cells are

contained in the walls of various organs
and tubes in the body, including the blood
vessels, stomach, intestines, bladder,
airways, uterus, and the penile and clitoral
cavernosal sinuses. When made to
contract, the smooth muscle cells shorten,
thereby propelling the luminal contents of
the organ, or the cell shortening varies the
diameter of a tube to regulate the flow of
its contents. There are also bundles of
smooth muscle cells attached to the hairs of
the skin and to the iris and lens of the eye.
When these bundles contract, the hairs
become erect and the lens of the eye
changes shape to focus light on the retina.

Smooth muscle cells lack the striated

banding pattern found in cardiac and
skeletal muscle, and they receive neural
innervation from the autonomic nervous
system. In addition, the contractile state of
smooth muscle is controlled by hormones,
autocrine/paracrine agents, and other local
chemical signals. Smooth muscle cells also
develop tonic and phasic contractions in
response to changes in load or length.
Regardless of the stimulus, smooth muscle
cells use cross-bridge cycling between actin
and myosin to develop force, and calcium
ions (Ca2+) serve to initiate contraction.

This brief review will serve as a refresher

for those educators who teach in medical
and graduate courses of physiology.
Additionally, those professionals who are in
need of an update on smooth muscle
physiology may find this review to be
useful. New concepts about regulatory
mechanisms are presented to add depth to
the understanding of the integrated
responses of contraction and relaxation in
smooth muscle. For those individuals
desiring a more in-depth treatment of the
subject, several recent reviews are
recommended (1, 3, 5, 7, 9, 10, 18).

THE CONTRACTILE MECHANISM

In the intact body, the process of smooth

muscle cell contraction is regulated
principally by receptor and mechanical
(stretch) activation of the contractile
proteins myosin and actin. A change in
membrane potential, brought on by the
firing of action potentials or by activation of
stretch-dependent ion channels in the
plasma membrane, can also trigger
contraction. For contraction to occur,
myosin light chain kinase (MLC kinase)
must phosphorylate the 20-kDa light chain
of myosin, enabling the molecular
interaction of myosin with actin. Energy
released from ATP by myosin ATPase
activity results in the cycling of the myosin
cross-bridges with actin for contraction.
Thus contractile activity in smooth muscle is
determined primarily by the
phosphorylation state of the light chain of
myosin—a highly regulated process. In
some smooth muscle cells, the
phosphorylation of the light chain of myosin
is maintained at a low level in the absence
of external stimuli (i.e., no receptor or
mechanical activation). This activity results
in what is known as smooth muscle tone
and its intensity can be varied.

Ca2+-DEPENDENT CONTRACTION
OF SMOOTH MUSCLE

Contraction of smooth muscle is initiated by

a Ca2+-mediated change in the thick
filaments, whereas in striated muscle Ca2+
mediates contraction by changes in the thin
filaments. In response to specific stimuli in
smooth muscle, the intracellular
concentration of Ca2+ increases, and this
activator Ca2+ combines with the acidic
protein calmodulin. This complex activates
MLC kinase to phosphorylate the light chain
of myosin (Fig. 1). Cytosolic Ca2+ is
increased through Ca2+ release from
intracellular stores (sarcoplasmic reticulum)
as well as entry from the extracellular
space through Ca2+ channels (receptor-
operated Ca2+ channels). Agonists
(norepinephrine, angiotensin II, endothelin,
etc.) binding to serpentine receptors,
coupled to a heterotrimeric G protein,
stimulate phospholipase C activity. This
enzyme is specific for the membrane lipid
phosphatidylinositol 4,5-bisphosphate to
catalyze the formation of two potent
second messengers: inositol trisphosphate
(IP3) and diacylglycerol (DG). The binding of
IP3 to receptors on the sarcoplasmic
reticulum results in the release of Ca2+ into
the cytosol. DG, along with Ca2+, activates
protein kinase C (PKC), which
phosphorylates specific target proteins.
There are several isozymes of PKC in
smooth muscle, and each has a tissue-
specific role (e.g., vascular, uterine,
intestinal, etc.). In many cases, PKC has
contraction-promoting effects such as
phosphorylation of L-type Ca2+ channels or
other proteins that regulate cross-bridge
cycling. Phorbol esters, a group of synthetic
compounds known to activate PKC, mimic
the action of DG and cause contraction of
smooth muscle. Finally, L-type Ca2+
channels (voltage-operated Ca2+ channels)
in the membrane also open in response to
membrane depolarization brought on by
stretch of the smooth muscle cell.
agonists(norepinephrine
angiotensinII,endothelin-1,etc.)
Ca?+
receptor

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voltage- lipaseC
operatedand (sarcoplasmic RhoGEF-
reticulum
receptor-
operatedCa2* +IP;DO RhoA-GTP RhoA-GDF
Cole
РКС (active) (inactivo,

Ca2*-*Ca2*/calmodulin
Rho-
MLCkinase Kinase ATP
(active)

actin+MLC(P)
contractedmyosin myosinP
oposonatase phosphatase
(active) mindcuve
MLC
(relaxed)

Caption 

Download figure | Download PowerPoint

Ca2+ SENSITIZATION MECHANISM

AND CONTRACTION OF SMOOTH
MUSCLE

In addition to the Ca2+-dependent

activation of MLC kinase, the state of
myosin light chain phosphorylation is
further regulated by MLC phosphatase [aka
myosin phosphatase (1, 4, 9, 11–16)], which
removes the high-energy phosphate from
the light chain of myosin to promote
smooth muscle relaxation (Fig. 1). There are
three subunits of MLC phosphatase: a 37-
kDa catalytic subunit, a 20-kDa variable
subunit, and a 110- to 130-kDa myosin-
binding subunit. The myosin-binding
subunit, when phosphorylated, inhibits the
enzymatic activity of MLC phosphatase,
allowing the light chain of myosin to remain
phosphorylated, thereby promoting
contraction. The small G protein RhoA and
its downstream target Rho kinase play an
important role in the regulation of MLC
phosphatase activity. Rho kinase, a
serine/threonine kinase, phosphorylates the
myosin-binding subunit of MLC
phosphatase, inhibiting its activity and thus
promoting the phosphorylated state of the
myosin light chain (Fig. 1). Pharmacological
inhibitors of Rho kinase, such as fasudil and
Y-27632, block its activity by competing
with the ATP-binding site on the enzyme.
Rho kinase inhibition induces relaxation of
isolated segments of smooth muscle
contracted to many different agonists. In
the intact animal, the pharmacological
inhibitors of Rho kinase have been shown
to cause relaxation of smooth muscle in
arteries, resulting in a blood pressure-
lowering effect (2, 17).

An important question facing the smooth-

muscle physiologist is: what is the link
between receptor occupation and
activation of the Ca2+-sensitizing activity of
the RhoA/Rho kinase-signaling cascade?
Currently, it is thought that receptors
activate a heterotrimeric G protein that is
coupled to RhoA/Rho kinase signaling via
guanine nucleotide exchange factors
(RhoGEFs; Fig. 1). Because RhoGEFs
facilitate activation of RhoA, they regulate
the duration and intensity of signaling via
heterotrimeric G protein receptor coupling.
There are ∼70 RhoGEFs in the human
genome, and three RhoGEFs have been
identified in smooth muscle: PDZ-RhoGEF,
LARG (leukemia-associated RhoGEF), and
p115-RhoGEF. Increased expression and/or
activity of RhoGEF proteins could augment
contractile activation of smooth muscle and
therefore play a role in diseases where an
augmented response contributes to the
pathophysiology (hypertension, asthma,
etc.).

Several recent studies suggest a role for

additional regulators of MLC kinase and
MLC phosphatase (13–16). Calmodulin-
dependent protein kinase II promotes
smooth muscle relaxation by decreasing
the sensitivity of MLC kinase for Ca2+.
Additionally, MLC phosphatase activity is
stimulated by the 16-kDa protein telokin in
phasic smooth muscle and is inhibited by a
downstream mediator of DG/protein kinase
C, CPI-17.

SMOOTH MUSCLE RELAXATION

Smooth muscle relaxation occurs either as

a result of removal of the contractile
stimulus or by the direct action of a
substance that stimulates inhibition of the
contractile mechanism (e.g., atrial
natriuretic factor is a vasodilator).
Regardless, the process of relaxation
requires a decreased intracellular Ca2+
concentration and increased MLC
phosphatase activity (Fig. 2) (10, 16). The
mechanisms that sequester or remove
intracellular Ca2+ and/or increase MLC
phosphatase activity may become altered,
contributing to abnormal smooth muscle
responsiveness.

Caption 

Download figure | Download PowerPoint

A decrease in the intracellular

concentration of activator Ca2+ elicits
smooth muscle cell relaxation. Several
mechanisms are implicated in the removal
of cytosolic Ca2+ and involve the
sarcoplasmic reticulum and the plasma
membrane. Ca2+ uptake into the
sarcoplasmic reticulum is dependent on
ATP hydrolysis. This sarcoplasmic reticular
Ca,Mg-ATPase, when phosphorylated,
binds two Ca2+ ions, which are then
translocated to the luminal side of the
sarcoplasmic reticulum and released. Mg2+
is necessary for the activity of the enzyme;
it binds to the catalytic site of the ATPase to
mediate the reaction. The sarcoplasmic
reticular Ca,Mg-ATPase is inhibited by
several different pharmacological agents:
vanadate, thapsigargin, and cyclopiazonic
acid. Sarcoplasmic reticular Ca2+-binding
proteins also contribute to decreased
intracellular Ca2+ levels. Recent studies
have identified calsequestrin and
calreticulin as sarcoplasmic reticular Ca2+-
binding proteins in smooth muscle.

The plasma membrane also contains

Ca,Mg-ATPases, providing an additional
mechanism for reducing the concentration
of activator Ca2+ in the cell. This enzyme
differs from the sarcoplasmic reticular
protein in that it has an autoinhibitory
domain that can be bound by calmodulin,
causing stimulation of the plasma
membrane Ca2+ pump.

Na+/Ca2+ exchangers are also located on

the plasma membrane and aid in
decreasing intracellular Ca2+. This low-
affinity antiporter is closely coupled to
intracellular Ca2+ levels and can be
inhibited by amiloride and quinidine.

Receptor-operated and voltage-operated

Ca2+ channels located in the plasma
membrane are important in Ca2+ influx and
smooth muscle contraction, as previously
mentioned. Inhibition of these channels can
elicit relaxation. Channel antagonists such
as dihydropyridine, phenylalkylamines, and
benzothiazepines bind to distinct receptors
on the channel protein and inhibit Ca2+
entry in smooth muscle.

ABNORMAL CONTRACTILE
REGULATION OF SMOOTH MUSCLE

Alterations in the regulatory processes

maintaining intracellular Ca2+ and MLC
phosphorylation have been proposed as
possible sites contributing to the abnormal
contractile events in smooth muscle cells of
various organs and tissues (2, 5, 8, 9). In
addition, alterations in upstream targets
that impact Ca2+ and MLC phosphorylation
have also been implicated. For example,
changes in the affinity, number, or subtype
of α-adrenergic receptors leading to
enhanced vasoconstriction have been
characterized in arterial smooth muscle
cells in some types of hypertension.
Increases in the activity of RhoA/Rho kinase
signaling lead to increased contractile
responses that may contribute to erectile
dysfunction in the penis and clitoris.
Increased activity of the RhoA/Rho kinase-
signaling pathway may also contribute to
augmented contraction or spastic behavior
of smooth muscle in disease states such as
asthma or atherosclerosis.

Impaired function may occur as the result of

a change in the direct action of a substance
that stimulates inhibition of the contractile
mechanism. For example, decreased
relaxation responses can be due to a
reduction in cyclic nucleotide-dependent
signaling pathways coupled with
reductions in receptor activation (β-
adrenergic receptors and cyclic AMP) or
agonist bioavailability (endothelium
dysfunction, reduced nitric oxide and cyclic
GMP). Importantly, it is the complexity and
redundancy of these cell signaling
pathways regulating intracellular Ca2+ and
MLC phosphorylation in smooth muscle
that provide therapeutic potential for
dysfunction.

SUMMARY

Smooth muscle derives its name from the

fact that it lacks the striations characteristic
of cardiac and skeletal muscle. Layers of
smooth muscle cells line the walls of
various organs and tubes, and the
contractile function of smooth muscle is not
under voluntary control. Contractile activity
in smooth muscle is initiated by a Ca2+-
calmodulin interaction to stimulate
phosphorylation of the light chain of
myosin. A Ca2+ sensitization of the
contractile proteins is signaled by the
RhoA/Rho kinase pathway to inhibit the
dephosphorylation of the light chain by
myosin phosphatase, maintaining force
generation. Removal of Ca2+ from the
cytosol and stimulation of myosin
phosphatase initiate the process of smooth
muscle relaxation.

This work was supported by grants from

the National Heart, Lung, and Blood
Institute (HL-18575 and HL-71138).

Address for reprint requests and other

correspondence: R. C. Webb, Dept. of
Physiology, Medical College of Georgia,
1120 Fifteenth St., Augusta, GA 30912–
3000 (E-mail: [email protected]).

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