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Hello, I am Dr. Andrew
Marks from Columbia University.
I would like to present
work from my laboratory
on mechanism-based
therapies for heart
failure and cardiac arrhythmias.
For the next 45 minutes or so, I
will review for you work that I
have done in the laboratory
over the past 20 years
that has focused on the ryanodine
receptor or cardiac calcium release
channel shown here, on
the right of this slide,
releasing small red balls that
represent the calcium that
drives muscle contraction.
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This cartoon, adapted from a
review by Dr. Donald Bers published
in Nature in 2002, shows
the basic mechanisms
of excitation-contraction
coupling that
involve the ryanodine receptor.
What is shown in this picture
is a cartoon or representation
of a heart muscle cell.
The action potential electrically
activates the heart muscle
and causes a depolarization of
the muscle membrane, which opens
a calcium channel that is blocked by
the clinically-used calcium channel
blockers.
Calcium entry from
outside the cell then
activates the much larger
ryanodine receptor,
or calcium release
channel, which is located
on the sarcoplasmic reticulum,
and it is the release of calcium
from the sarcoplasmic reticulum
that raises the
concentration of calcium
in the muscle cell
approximately 10 times,
and this is the
signal that activates
the contraction of the
myofilaments to cause
the contraction of heart muscle.
A similar mechanism
works in skeletal muscle.
So this is the mechanism whereby the
electrical energy from the action
potential is translated
into a mechanical energy
that causes muscle contraction.
About 20 years ago, as
I will describe to you,
I discovered a small
regulatory protein
that we now call calstabin,
or calcium release channel
stabilizing binding protein,
and it is also known as the
FK binding protein or FKBP.
And this calstabin, or FKBP,
has several critically-important
functions in regulating the calcium
release channel that I will soon
describe to you and has become
an important therapeutic target
for both heart failure
and sudden cardiac death.
