CHAPTER 3 • CELLULAR STRUCTURE AND FUNCTION
47
Epi
Ado
■ FIGURE 3.6 Signal transduction pathways regulating cardiac m yocyte contraction. The two major path-
ways involve form ation of either cyclic adenosine monophosphate (cAMP) or inositol 1,4,5-triphosphate
(IP3), both of which affect Ca++ release by sarcoplasmic reticulum and therefore affect contraction.
R,
recep-
tor;
Gs,
stim ulatory G-protein;
Gi,
inhibitory G-protein;
Gq,
phospholipase C-coupled G-protein; AC, adenylyl
cyclase;
PL-C,
phospholipase C;
PIP2,
phosphatidylinositol 4,5-bisphosphate;
DAG,
diacylglycerol;
PK-C,
protein kinase C;
PK-A,
protein kinase A;
SR,
sarcoplasmic reticulum;
ATP,
adenosine triphosphate;
NE,
norepinephrine;
AIl,
angiotensin II;
ET-1,
endothelin-1;
Epi,
epinephrine;
ACh,
acetylcholine;
Ado,
adenosine.
activation, PK-A phosphorylates sites on the
sarcoplasmic reticulum, leading to an increase
in calcium release.
Besides the cAMP pathway, a second path-
way within myocytes can affect calcium release
by the sarcoplasmic reticulum, although this
pathway appears to be less important physi-
ologically than the cAMP/PK-A pathway. This
second pathway involves a class of G-proteins
(Gq-proteins; Fig. 3.6) that are associated with
^-adrenoceptors (bind norepinephrine), angi-
otensin II receptors (AT1), and endothelin-1
receptors (ETA). Activation of these receptors
stimulates phospholipase C to form inositol
triphosphate (IP3) from phosphatidylinositol
4,5-bisphosphate (PIP2), which stimulates cal-
cium release by the sarcoplasmic reticulum.
CALCIUM BINDING TO TN-C
Another
mechanism
by
which
inotropy
can be modulated is by altered binding of
calcium to TN-C (Fig. 3.5, site 3). The bind-
ing of calcium to TN-C is determined by the
free intracellular concentration of calcium
and the binding affinity of TN-C to calcium.
The greater the intracellular calcium concen-
tration, the more the calcium that is bound
to TN-C, and the more the force that is gen-
erated between actin and myosin. Increasing
the affinity of TN-C for calcium increases
binding at any given calcium concentra-
tion, thereby increasing force generation.
Acidosis, which occurs during myocardial
hypoxia, has been shown to decrease TN-C
affinity for calcium. This may be one mecha-
nism by which acidosis decreases the force of
contraction.
Changes in calcium sensitivity may explain
in part how increases in sarcomere length
(also known as preload; see Chapter 4) leads
to an increase in force generation. It appears
that
increased
preload
increases
calcium
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