Molecular Evolution of Novel Ion Channel
Inhibitors and Activators
We
run on electricity. Brains, muscles, hearts, and senses
all require electrical signals to function properly.
Our research aims to understand the basic components
of excitable cells that are responsible for generating
electrical activity. To this end, we focus on understanding
the structure, function, and regulation of ion channels
from a high-resolution viewpoint. Our lab is multidisciplinary
and combines approaches that include X-ray crystallographic
studies, biochemistry, molecular biology, selection
from combinatorial libraries, and electrophysiology
to understand the basic mechanisms of how these proteins
function and are regulated.
Ion
channels are membrane proteins that allow cells to
generate electrical signals. They are found not only
in excitable cells like neurons and muscle, but are
ubiquitous in biological systems. These proteins act
as gates, specifically controlling the flux of ions
across the cell's membrane in the response to a variety
of stimuli including transmembrane voltage changes,
ligand binding, and second messenger stimulation.
Generally, channel proteins exist in one of two conformations,
open or closed. In the open state, ion channels form
a pathway that allows ions flow down their electrochemical
gradients from one side of the cell membrane to the
other. Control of ion flux in response to external
stimulation, generates the fundamental signaling step
that forms the basis for many biological processes
such as the regulation of heartbeat, movement of muscle,
regulation of hormone release from pancreatic cells,
and the generation of thought. Many types of ion channels
are known. Channels that specifically conduct potassium
ions constitute the largest, most diverse family of
ion channels and play key roles in the regulation
of cell excitability. We are interested in understanding
the mechanisms by which these proteins act. What are
principal rules that govern ion channel structure?
What is the nature of the conformational changes that
accompany channel activation? How does a cell modulate
channel activity through the action of proteins like
kinases and GTPases? Can we develop new methods to
modulate ion channel function in vivo? Addressing
the molecular basis of these issues will be critical
to understanding the roles of ion channels in larger
signaling networks, like the brain, as well as understanding
their misfunction in various human diseases.
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