Perelman School of Medicine Affiliations
Department of Cell and Developmental Biology
Cell and Molecular Biology Graduate Group
Neuroscience Graduate Group
B.S., Duke University, 1974
M.S., University of South Carolina, 1977
Ph.D., University of California, Berkeley, 1981
Designated Ion Channel Lecturer of the Physiological Society
Canadian Cystic Fibrosis Foundation Scholar
Society of General Physiologists
American Physiological Society
American Association for the Advancement of Science
Our laboratory is interested in mechanisms of ion permeation
across cell membranes and intracellular signaling, particularly
in epithelial cells, and the roles of these processes in
diseases, including cystic fibrosis. The lab has two distinct
major foci of research efforts:
Cystic Fibrosis. Cystic fibrosis (CF) is the most common potentially
disease among Caucasians. Although
the spectrum of clinical manifestations is quite wide,
an underlying basis of CF is abnormal regulation of ion
fluid transport by epithelial cells in organs which are
severely affected in the disease, including the lungs,
tract and intestines. The CF gene product (CFTR) is a cAMP-regulated
Cl- ion channel that is expressed in the apical membranes
of epithelial cells. Our research focuses on understanding
the activities, regulation and roles of the normal and
mutant cystic fibrosis gene product. Our recent efforts
on identifying proteins that interact with CFTR, and elucidating
the consequences of these protein-protein interactions.
Our hope is that by understanding the nature of the complex
proteins with which CFTR interacts, we may discover novel
insights that could be exploited for therapeutic purposes.
In the future, students and fellows in the lab could consider
these research areas: developing genomic-scale approaches
to discover therapeutic proteins in cells; developing physiological
approaches to examine the functions of CFTR in intact tissues;
and studying the single channel properties of CFTR to determine
its oligomeric structure and to define the ion permeation
pathway. Our research has been funded by grant support
from the NIH and the Cystic Fibrosis Foundation.
Calcium signaling. The second focus of the group
is understanding the molecular physiology of intracellular
signaling by Ca2+,
with a particular focus on unique approaches for studying
the properties and regulation of intracellular Ca2+ release
channels, especially inositol trisphosphate receptors,
and their roles in normal and pathological cell physiological
states. The inositol trisphosphate receptors are a family
of proteins expressed in all cells, that participate
Ca2+ signals which can be manifested as highly localized
subcellular events or more globally throughout cells,
often as highly complex signals with exquisite patterns
in both space and time. These signals participate in
normal cell physiological processes, including mitosis,
secretion and gene transcription, and in pathological
states, including epilepsy, Alzheimer's disease and programmed
cell death (apoptosis). We have developed novel techniques
study the properties of single inositol trisphosphate
ion channels, and we have recently developed new expression
systems to enable the study of recombinant isoforms.
An important goal is to relate the behaviors of the channels
to the properties
of the cytoplasmic Ca2+ signals that they generate. In
addition, we wish to understand the molecular details
regulation of channel gating activity. We are also attempting
to discover the molecular mechanisms that enable calcium
signals to be highly localized in cells. In the future,
students and fellows in the lab could consider these
identifying protein complexes associated with the InsP3
receptor and analyzing the functional implications; investigating
the structure-function relationships of the channel to
how the channel is regulated and the mechanisms of ion
permeation and channel gating; development of animal
models. This research
is funded by the NIH. Additional support to examine the
roles of ion channels in apoptosis and AIDS has been
the Dept. Defense Breast Cancer Initiative and the Penn
Center for AIDS Research.
The techniques we employ in the lab span the spectrum from biophysical
Biochemical and molecular
are used within the context of physiological measurement,
with the goal to understand how molecular behavior
results in complex cell physiological processes in normal
disease states. We employ electrophysiology, including
channel patch clamping and two-electrode voltage clamping;
digital low light-level fluorescence imaging microscopy
of single living cells; micro-injection; yeast 2-hybrid
to examine and discover protein interactions; recombinant
protein expression; molecular biology; and biochemistry.
J., S. McBride, D.-O. D. Mak, F. Haeseleer, K. Palczewski and
J. K. Foskett. 2002. Identification of a family of
calcium sensors as protein ligands of inositol trisphosphate
receptor Ca2+ release channels. Proc. Nat. Acad. Sci. 99:7711-7716.
K.R., J. E. McCane. L.A. Witters. and J.K. Foskett. 2003.
AMP-activated protein kinase modulates cystic fibrosis
transmembrane conductance regulator activity in lung
submucosal cells by effects on channel gating. J. Biol.
W., D.O.D. Mak, Q. Li, D. M. Shin, J. K. Foskett and S.
Muallem. 2003. A new mode of Ca2+
G protein-coupled receptors: Gating of IP3 receptor
Ca2+ release channels by Gbg. Current Biol. 13:872-876.
V., H. Hormuth and J.K. Foskett. 2003. A kinase-regulated
mechanism controls CFTR channel gating
bivalent PDZ domain interactions. Proc. Nat. Acad.
D.O.D, S. McBride, N.B. Petrenko and J.K. Foskett. 2003.
Novel regulation of calcium inhibition
inositol 1,4,5-trisphosphate receptor calcium release
J. Gen. Physiol 122: 569-581.
D.O.D, S. McBride and J.K. Foskett. 2003. Spontaneous channel
gating of the
(InsP3) receptor (InsP3R). Application of allosteric
to calcium and InsP3 regulation of InsP3R single-channel
J. Gen. Physiol. 122:583-603.
Click here for
a full list of publications
(searches the National Library of Medicine's PubMed database.)