The sarcoplasmic reticulum (SR) is one of the major regulators of the
cytosolic Ca2+ concentration in cardiac ventricular muscle cells. In the
myocardium, relaxation results from a decrease in cytoplasmic free Ca2+ levels
mediated through an efflux of Ca2+ from the cell via the sarcolemmal Na+/Ca2+-
exchanger and by the sequestration of 0a2+ by the network SR membranes through
the actions of a calcium pump (a Mg2+dependent, Ca2+/K+activated adenosine
triphosphatase; Ca2+/K+-ATPase). During an action potential, the Ca2+ stored in
the SR is released to the cytoplasm via a Ca2+release channel present in the
junctional SR and Ca2+ also enters the cell through voltage-controlled Ca2+
channels in the sarcolemmal membrane. These two processes result in an increase
in cytoplasmic Ca2+ concentration which leads to contraction of the myocardium.
SR membrane function is regulated in part by the phosphorylation of
proteins present in this membrane. Subsequent to 3-adrenergic stimulation of the
heart by catecholamines, levels of cAMP are increased leading to the activation of
cAMP-dependent protein kinase (PK A). In isolated cardiac SR membrane vesicles
and perfused hearts, phosphorylation of an indigenous SR protein, phospholamban,
is mediated by PK A. Phosphorylated phospholamban acts as a modulator of the
Ca2+/K+-ATPase to stimulate active Ca2+ uptake by increasing the affinity of this
enzyme for Ca2+. This stimulation of Ca2+-uptake is the main mechanism by
which catecholamines accelerate relaxation in the heart. When phospholamban is
in the dephosphorylated state, a cytoplasmic portion of the molecule interacts near
the phosphorylation site of the Ca2+-pump to inhibit Ca2+-transport.
[More abstract follows]Pharmaceutical Sciences, Faculty ofGraduat
