chapter 21
Muscle and Nonmuscle Contractile Systems
Twitch duration is largely a function of how extensive
the SR is. In FT fibers, SR accounts for roughly 15% of the
cell volume, whereas it is only about 3-5% in ST fibers.
The total RyR Ca2+ conductance and the total SR Ca2+-
ATPase activity reflects this, so that the rates of Ca2+ re-
lease in the E-C coupling phase, the peak sarcoplasmic
[Ca2+] achieved in a twitch, and the reuptake rate of Ca2+
are all
times greater in FT fibers than in ST fibers.
These differences result in the shorter time to peak tension,
higher twitch tension, and shorter half-relaxation time seen
in FT fibers compared to ST.
The ATP-dependent Ca2+ pump of SR (sarcoplas-
mic/endoplasmic reticulum Ca2+-ATPase, or SERCA) be-
longs to a group of ion pumps called the P class, which
typically have four transmembrane subunits, two large
a-subunits and two /3-subunits. The a-subunit is phos-
phorylated during the transport process, and the trans-
ported ion is believed to move through this protein. This
class includes the ubiquitous Na+, K+-ATPase and the
plasma membrane Ca2+-ATPase. In SR, this pump appar-
ently occurs as a single a-subunit with a molecular weight
of 100,000, coupled to a smaller protein called
These are densely packed on regions of the SR
and account for 60-80% of the transmembrane protein in
SR. SERCA transports 2 Ca2+ for each ATP hydrolyzed
and has very high affinity for Ca2+ on its sarcoplasmic
about 0.1 gM); this allows the protein to pump
the sarcoplasmic [Ca2+] to the 0.1 gM range and below.
Phospholamban regulates the activity of the pump, prob-
ably by regulating the affinity of the a-subunit for Ca2+.
Phosphorylation of phospholamban increases the Ca2+-
ATPase activity 10- to 100-fold.
Three SERCA genes are known. The SERCA 1
produces two isoforms via alternative splicing (SERCA 1
and SERCA lb) which are found in adult FT fibers and
neonatal fibers, respectively. SERCA2 also produces two
proteins by alternative splicing, SERCA2a and SERCA2b,
which are found in ST/cardiac fibers and smooth muscle,
respectively. SERCA3 is found in the ER of most non-
muscle tissue.
Mechanism of Contraction: Activation
of Contraction
As described above, depolarization leads to transient Ca2+
release from SR. As sarcoplasmic [Ca2+] rises, so does
Ca2+ binding to Tn C. As Tn C saturates with Ca2+, it
reverses the tropomyosin inhibition of myosin binding to
actin. Our current understanding is that this occurs by a
small movement of the tropomyosin induced by the di-
mensional change that occurs in Tn C upon Ca2+ bind-
ing, thus relieving a steric block. However, a mechanism
h e a d
h e a d
tro p o n in
tro p o m y o s in
T ropo m yo sin
tro p o n in
Schematic the interaction of myosin and actin. (a) In the absence of Ca2+,
tropomyosin prevents the binding of myosin heads to actin. (b) When the
[Ca2+] rises, Ca2+ binds to a subunit of troponin, which causes the
tropomyosin to shift slightly into the groove of the actin thin filament. The
shift in position of tropomyosin allows the myosin heads to bind to actin.
Lowering of the [Ca2+] results in reversal of these events.
based on more subtle interactions between tropomyosin
and actin cannot be ruled out (Figure 21-9). The result is
that myosin heads are able to contact actin with forma-
tion of active cross-bridges and generation of tension. The
initiation of cross-bridge formation by calcium is called
activation of contraction.
Activation becomes detectable
at a [Ca2+]j of about 0.1
is half-maximal at 1 ju,M,
and plateaus at 10
SR reuptake of calcium poststim-
ulus lowers sarcoplasmic [Ca2+], desaturating the Tn C
and allowing the tropomyosin inhibition of cross-bridge
formation to be reasserted. It has recently been shown that
nebulin (see subsection Myofibrils, p. 457) can inhibit
actomyosin ATPase activity, preventing actin from being
physically translated by myosin, and that this inhibition
can be reversed by Ca-CaM. This suggests a possible thin
filament-linked regulation in striated muscle.
Mechanism of Contraction:
Cross-Bridge Cycling
The nature of the S2 region allows the myosin heads
to be in very close proximity to the actin. When the
tropomyosin-mediated inhibition of contraction is re-
versed, the myosin heads interact strongly with actin. Al-
though there is still debate over the details of how this
interaction produces mechanical work, there is a consen-
sus on the general outline. Myosin bonds initially via rela-
tively flexible loop regions near the catalytic site, followed
by progressively more extensive hydrogen bonding. In
this process, a large surface area on each protein (totaling
15-20 nm2) is removed from interaction with cell water
during formation of the bond between them. In cases where
proteins bond without changes in conformation, burying
this much area would be associated with an energy change
of 60-80 kJ/mol of bonds, a number roughly twice as great
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