Irwin
B. Levitan, Ph.D.
David Mahoney Professor and Chair,
Dept of Neuroscience
School of Medicine
Director, The Mahoney Institute of Neurological Sciences
Suite 215 Stemmler Hall/6074
email: levitani@mail.med.upenn.edu
Molecular mechanisms of regulation of neuronal excitability; modulation
of neuronal ion channels; role of ion channel modulation in behavior
RESEARCH TECHNIQUES
Molecular, biochemical and biophysical characterization of ion channels
and associated signaling proteins; antibody generation and characterization;
co-immunoprecipitation; molecular cloning and mutagenesis; mammalian cell
culture; bacterial and mammalian cell expression; yeast two-hybrid screens;
patch clamp and voltage clamp analysis of ion channel activity in neurons
and heterologous cells; Drosophila genetics, electrophysiology and
behavior
RESEARCH SUMMARY
My laboratory is interested in the long term regulation of neuronal excitability
and synaptic transmission. We study the molecular mechanisms that nerve
cells use to modulate the activity of individual ion channels, since these
mechanisms must contribute to long term changes in neuronal function and
ultimately in behavior. The essence of our approach is a combination of
biochemistry, molecular biology, genetics and electrophysiology, at the
level of individual neurons, synapses and ion channels. We study the electrophysiological
properties of native channels in neurons, and of cloned channels expressed
in heterologous host cells, using patch recording techniques. In parallel
we carry out biochemical measurements of channel proteins, making use of
specific antibodies directed against channel epitopes. One theme that we
are pursuing vigorously is the idea that channels do not exist on their
own in the plasma membrane, but rather are part of a regulatory complex
that includes signaling proteins that are involved in the modulation of
channel function. For example, we have found that the Src tyrosine kinase,
the catalytic subunit of cyclic AMP-dependent protein kinase and the ubiquitous
calcium sensor calmodulin all bind directly to potassium channels and influence
their function. We also have isolated a novel protein named Slob, which
binds to and modulates the Slowpoke calcium-dependent potassium channel.
We are investigating the molecular details and physiological significance
of the dynamic interactions of Slob, the protein kinases, calmodulin and
other signaling proteins with several different kinds of potassium channels.
One way we do this is by using genetics to introduce mutant channels and
their binding partners into flies and ask questions about the roles of ion
channel regulatory complexes in neuronal physiology and behavior.

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