Other Perelman School of Medicine Affiliations
Department of Cell and Developmental Biology
Cell and Molecular Biology Graduate Group
Neuroscience Graduate Group

Degrees
B.S., Duke University, 1974
M.S., University of South Carolina, 1977
Ph.D., University of California, Berkeley, 1981

Honors
Designated Ion Channel Lecturer of the Physiological Society
Canadian Cystic Fibrosis Foundation Scholar

Professional Affiliations
Society of General Physiologists
American Physiological Society
Biophysical Society
American Association for the Advancement of Science

Research Description
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:

a) Cystic Fibrosis. Cystic fibrosis (CF) is the most common potentially lethal genetic disease among Caucasians. Although the spectrum of clinical manifestations is quite wide, an underlying basis of CF is abnormal regulation of ion and fluid transport by epithelial cells in organs which are severely affected in the disease, including the lungs, pancreas, reproductive 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 have been 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 of 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.

b) 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 in generating Ca2+ signals which can be manifested as highly localized subcellular events or more globally throughout cells, often as highly complex signals with exquisite patterns generated in both space and time. These signals participate in normal cell physiological processes, including mitosis, motility, secretion and gene transcription, and in pathological states, including epilepsy, Alzheimer's disease and programmed cell death (apoptosis). We have developed novel techniques to study the properties of single inositol trisphosphate receptor 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 involved in the 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 research areas: identifying protein complexes associated with the InsP3 receptor and analyzing the functional implications; investigating the structure-function relationships of the channel to determine 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 provided by 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 to molecular. Biochemical and molecular tools are used within the context of physiological measurement, with the goal to understand how molecular behavior results in complex cell physiological processes in normal and disease states. We employ electrophysiology, including single ion channel patch clamping and two-electrode voltage clamping; digital low light-level fluorescence imaging microscopy of single living cells; micro-injection; yeast 2-hybrid system to examine and discover protein interactions; recombinant protein expression; molecular biology; and biochemistry.

Representative Publications
Yang, 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.

Hallows, 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. Chem 278:998-1004.

Zeng, W., D.O.D. Mak, Q. Li, D. M. Shin, J. K. Foskett and S. Muallem. 2003. A new mode of Ca2+ signaling by G protein-coupled receptors: Gating of IP3 receptor Ca2+ release channels by Gbg. Current Biol. 13:872-876.

Raghuram, V., H. Hormuth and J.K. Foskett. 2003. A kinase-regulated mechanism controls CFTR channel gating by disrupting bivalent PDZ domain interactions. Proc. Nat. Acad. Sci. 100:9620-9625.

Mak, D.O.D, S. McBride, N.B. Petrenko and J.K. Foskett. 2003. Novel regulation of calcium inhibition of the inositol 1,4,5-trisphosphate receptor calcium release channel. J. Gen. Physiol 122: 569-581.

Mak, D.O.D, S. McBride and J.K. Foskett. 2003. Spontaneous channel gating of the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R). Application of allosteric modeling to calcium and InsP3 regulation of InsP3R single-channel gating. J. Gen. Physiol. 122:583-603.

Click here for a full list of publications
(searches the National Library of Medicine's PubMed database.)