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Phospholamban
Phospholamban
(PLN) is a 52 amino acid protein of 6.1 kDa that forms a homopentamer.
In the dephosphorylated state, it is an inhibitor of SERCA2a activity,
but inhibition is relieved upon phosphorylation of PLN. In vitro studies
indicated that PLN can be phosphorylated at three distinct sites by various
protein kinases: serine 10 (Ser10), by protein kinase C; serine 16 (Ser16),
by cAMP- or cGMP-dependent protein kinase; and threonine 17 (Thr17), by
Ca2+-calmodulin-dependent protein kinase. Phosphorylation of PLN is associated
with stimulation of the initial rates of cardiac sarcoplasmic reticulum
Ca2+ uptake at low Ca2+, resulting in an overall increase in the affinity
of the SERCA2a for Ca2+.
The role of PLN in the regulation of basal contractility has been elucidated
through the development of genetically engineered mouse models. Characterization
of the cardiac phenotype of our PLB-knockout mice indicated that PLN is:
a) a key determinant of the affinity of the SR Ca2+-ATPase for Ca2+; and
b) a major regulator of calcium homeostasis and contractility in cardiac,
smooth and slow-twitch skeletal muscles. PLN is also a key mediator of
the b-adrenergic responses in the heart. Furthermore, using transgenic
technology, we generated mice with cardiac-specific or fast-twitch skeletal
muscle-specific overexpression of PLN. Characterization of these models
indicated that: a) only a fraction of the cardiac sarcoplasmic reticulum
calcium-pumps is under regulation by PLN in vivo, suggesting that this
may constitute an important "brake mechanism" in the heart;
and b) ectopic expression of PLN in fast-twitch skeletal muscles results
in depressed Ca2+-transients and contractility (See Figure Below). These
models with altered Ca2+ homeostasis and contractility have been valuable
tools for our research group and other laboratories around the nation
to test specific hypotheses and further define the mechanisms regulating
excitation-contraction coupling in muscle.
Schematic representation of the effects
of PLN ablation and overexpression in the heart.
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