Molecular Physiology and Biophysics Section
Dr. Swartz received his B.S. degree in Chemistry and Biology in 1986 from Eastern Mennonite College. In 1992 he received his Ph.D. in Neurobiology from Harvard University where he worked with Bruce Bean studying the regulation of voltage-gated calcium channels by G-proteins and protein kinases. He did postdoctoral training with Roderick MacKinnon at Harvard Medical School, where he began isolating and studying toxins that interact with voltage-activated potassium channels. Dr. Swartz joined NINDS as an Investigator in 1997 and was promoted to Senior Investigator in 2003. His laboratory is using biochemical, molecular biological and biophysical techniques to investigate the structure of voltage-activated ion channels and to explore the molecular mechanics by which these channels gate.
The research focus of the laboratory is to understand how ion channel
proteins sense critical biological stimuli, including membrane voltage,
temperature and chemical signals. Understanding the structure and mechanisms of
voltage-activated ion channels is of fundamental importance because these
proteins generate nerve impulses and thereby enable neurons to signal rapidly
over long distances. A mechanistic understanding of these proteins is of
medical significance because they are involved in many diseases, and are widely
targeted by therapeutic drugs. X-ray structures of voltage-activated potassium
(Kv) channels in activated/open states have led to new ideas about how interactions
between voltage-sensing domains and the lipid membrane may be crucial for the function
of these channels. We are exploring this theme using a range of approaches,
including using tarantula toxins that bind to voltage-sensing domains within
the membrane to
investigate the protein-lipid interface and solve the structure of a
resting/closed state. We have also discovered a new protein that contains an
identifiable S1-S4 voltage-sensing domain and large cytoplasmic termini, which
we named Coupled Voltage Sensor (CVS). Our results suggest that CVS is a
functional voltage sensor, and we are currently testing the hypothesis that CVS
interacts with a intracellular signaling pathways. We also study the mechanism
by which transient receptor potential (TRP) channels sense changes in
temperature, a mechanism that is critical for their biological roles in thermoregulation
and detection of noxious stimuli. Studies with tarantula toxins and regulatory ion
binding sites point to a critical role of the external pore in the gating
mechanisms of TRPV1, and we
are working to localize the temperature sensor and understand its mechanism. Our
efforts to understand the structure and operational mechanisms of
ligand-activated ion channels involved in intercellular communication has focused
on P2X receptor channels, a family of trimeric cation channels that are
activated by extracellular ATP. Thus far we have explored the structure and
dynamics of the pore, and
investigated whether the pore undergoes dilation in response to continual
activation. We are currently
exploring two distinct mechanisms by which divalent cations differentially regulate
either by binding along with ATP and determining the forms of ATP that serve as
agonists, or by binding within an unusual chamber within the large
extracellular domain to regulate the process of opening or desensitization.
Chanhyung Bae, Ph.D.
Angela Ballesteros Morcillo, Ph.D.
Tsg-Hui (Helena) Chang, M.Sc
Ana Fernandez-Marino, Ph.D.
Benjamin George, B.S.
Post baccalaureate Fellow
Kanchan Gupta, Ph.D.
Kate Huffer, B.S.
Post baccalaureate Fellow
Andres Jara-Oseguera, Ph.D.
Tamas Lajtos, M.Sc
Mufeng Li, Ph.D.
Suvendu Lomash, Ph.D.
Shai Silberberg, Ph.D.
Orsolya Szilagyi, Ph.D.
Gil Toombes, Ph.D.
Feng Zhang, Ph.D.