Thomas P. Flagg, Ph.D., Instructor
Research
In the heart, the coordinated action of ion channels and
transporters is essential for maintaining both the regular
heart rhythm and providing the stimulus for cardiac contraction.
A number of ion channel mutations, in recent years, have been
linked with diseases that are characterized by abnormal cardiac
conduction and sudden cardiac death. ATP-sensitive potassium
channels are expressed at a very high density in the myocardium.
Normally silent in the myocardium, KATP channels become active
during severe metabolic stresses, like myocardial ischemia.
Given the high incidence of arrhythmia following ischemia,
it is likely that KATP channels play a role in either promoting
or preventing rhythm disturbances. Using a combination of
functional genomics, molecular biology, and patch clamp electrophysiology,
I am studying cardiac KATP channels to determine their function
in the heart during normal and disease states.
Currently, these projects fall into three major areas:
1) Functional remodeling of ion channels in the myocardium
The concept of ion channel remodeling (changes in ion channel
gene expression) as a consequence of disease is well established.
We have generated transgenic mice that express ATP-insensitive
(“overactive”) KATP channels in the heart. Based
on the current computer models of the cardiac action potential,
it was predicted that expression of this channel would significantly
shorten the action potential and reduce contractility. Instead,
action potential duration is maintained and contractility
is increased, by a compensatory stimulation of ICa. Importantly,
this does not appear to require changes in gene expression.
Currently, we are working to understand the molecular mechanisms
that link KATP and ICa.
2) Exploring differences between pancreatic and cardiac KATP
channel physiology
Expression of “overactive” KATP channels in the
pancreatic ?-cell cause neonatal diabetes in mice and humans.
In the heart, similar gain-of-function mutants have little
effect, suggesting that differences in KATP structure are
important in determining channel physiology. We are currently
using transgenic mice that overexpress the pancreatic channel
subunits in the heart to determine what functions the unique
structure of cardiac KATP channels contributes to the physiology
of the heart. Shown below is a representative electrocardiogram
from a mouse that expresses both SUR1 and an ATP-insensitive
Kir6.2 subunits showing persistent second degree AV conduction
block that results from changing the electrical substrate
of the heart and ultimately results in sudden premature death.
3) KATP channel assembly and trafficking
All of the known subunits of KATP channels are expressed
in the in heart, yet the principal KATP channel in the heart
is composed of SUR2A and Kir6.2. This suggests a specificity
of channel assembly or trafficking that has not yet been explored.
We are currently examining the assembly of cardiac KATP channels
from the individual components to identify the molecular mechanisms
that determine the specificity of cardiac KATP structure.
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