464
chapter
21
Muscle and Nonmuscle Contractile Systems
SR Ca2+-ATPase, where there is one gene expressed in
FT fibers, called SERCA1, and another in ST and cardiac
fibers, called SERCA2.
Nucleotide sequences of multiple copies of genes tend
to diverge over time. However, the primary structure
of actin must be conserved, as mentioned earlier, due
to the large number of specific binding sites in relation
to the number of amino acids. The sequence of actin from
the slime mold
Physarum polycephalum
differs only 8%
from that of mammalian skeletal muscle actin. The various
myosin families vary much more, especially in their tail
and neck regions, and some have only one heavy chain.
The number of light chains can vary from one to six. How-
ever, there is much less variation in myosin II. For example,
the repeat structure of the tail regions in the muscle MHCs
is highly conserved, and there are several segments of the
actin binding and ATPase sites in the heads that are con-
served not only within the myosin II subfamily, but across
myosin families. There are also striking structural simi-
larities between the heads of myosin and the microtubule
motor kinesin despite a general lack of sequence similar-
ity, and there are some key sequences in the nucleotide
binding regions that are highly conserved.
G-proteins
are
another class of proteins that, like myosin heads, link two
other structures in a nucleotide-dependent manner, and
G-proteins also strongly resemble myosin heads struc-
turally and have striking sequence homology in the re-
gion of the nucleotide binding site. Thus, these molecular
motors and the G-proteins share structural features, and it
is likely that insight into one will increase understanding
of the others.
21.2 Mechanism of Muscle
Contraction: Overview
Our current understanding of the mechanism of contrac-
tion is reflected in th
q sliding filament model
and the
cross-
bridge hypothesis.
The sliding filament model holds that
the shortening of sarcomeres characteristic of contraction
in muscle is due to the sliding of the thick and thin fila-
ments past one another due to interactions between them,
such that the thin filaments are pulled toward the center of
the thick filament array. This movement between filaments
is believed to be driven by interaction between the myosin
heads and the thin filaments in which the binding of myosin
to actin, or cross-bridge formation, triggers changes in the
head structure that create mechanical tension. This is the
cross-bridge hypothesis.
One prediction of this model of
contraction is that the tension elicited by stimulation of
a muscle will depend on the degree of overlap between
thick and thin filaments, since this would determine the
number of cross-bridges that can be formed. Thus, there
would be a characteristic relation between length and iso-
metric tension, which is, in fact, observed. For signifi-
cant shortening to occur by this mechanism, cross-bridges
must repeatedly form, create tension, be broken, and re-
form. This is called cross-bridge cycling. The speed of
sarcomere shortening depends on the mean cross-bridge
cycling rate. Since the early 1960s, methods of study-
ing the contraction mechanism have become increasingly
sophisticated; recent developments such as optical traps
or laser tweezers allow measurement of force (usually
5-10 piconewtons) and movement (from 5-11 nm) pro-
duced by a single myosin head acting on an actin filament.
Mechanism of Contraction:
Excitation/Contraction Coupling
The primary intracellular event in the activation of con-
traction is an increase in [Ca2+]j in the sarcoplasm from a
resting level of about 0.05 /xmol/L to about 5 /xmol/L or
more during repetitive stimulation. This Ca2+ surge can be
elicited by a-MN stimulation or by direct electrical stim-
ulation of the fiber. The details of how this occurs differ
greatly between skeletal, cardiac, and smooth muscle. In
skeletal muscle, an action potential from an a-MN in the
ventral horn of the spinal cord triggers acetylcholine (Ach)
release from the presynaptic membrane. At the postsynap-
tic membrane, binding of Ach to its receptors depolarizes
the membrane to threshold, initiating an action potential
that propagates all along the sarcolemma and down the
/-tubules. This depolarization results in Ca2+ release from
the sarcoplasmic reticulum. The abundant SR Ca-ATPase
creates a concentration ratio from SR to sarcoplasm of
104 to 105, so that the release of Ca2+ requires only that
the SR conductance to Ca2+ be increased. The connec-
tion between depolarization and Ca2+ release is called
excitation-contraction (or E-C) coupling.
A component
of botulinum toxin (Botox) cleaves synaptobrevin, a pro-
tein required for docking of transmitter vesicles to the
presynaptic membrane. Botox blocks Ach release, causing
paralysis. It is used to treat spasticity, tremor, hypertonia,
and other muscle conditions of localized hyperactivity.
E-C coupling involves a large protein in the t-tubular
membrane called the DHP receptor (DHPR), and another
protein in the SR membrane of the terminal cistern called
the ryanodine receptor (RyR). The DHPR has been shown
to be a voltage-gated Ca2+ channel. It has an
a
i subunit
similar to the voltage-dependent fast Na+ channel, and
four other proteins, with a total molecular weight of
~415,000. The RyR has four large subunits, each with a
molecular weight of about 565,000. It has been shown to
be a ligand-gated Ca2+ channel, for which an operative
