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J. Kevin Foskett, PhD

J. Kevin Foskett, PhD

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Isaac Ott Professor of Physiology
Department: Physiology
Graduate Group Affiliations

Contact information
Department of Physiology
University of Pennsylvania
Perelman School of Medicine
700D Clinical Research Bldg./ 6085
Philadelphia, PA 19104
Office: (215) 898-1354
Fax: (215) 573-2273
Duke University, 1974.
University of South Carolina, 1977.
University of California at Berkeley, 1981.
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Description of Research Expertise

Research Interests
Ion channels, calcium signaling, cystic fibrosis, Alzheimer's disease, mitochondrial bioenergetics

Key Words: signal transduction, genetic disease, ion channel, calcium, cystic fibrosis, electrophysiology, Alzheimer's, mitochondria.

Description of Research
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.

Lab personnel (6/24/14):
Dr. Daniel Mak, PhD (Senior Research Investigator)
Dr. Zhongming Ma (Senior Research Investigator)
Dr. Jessica Tanis (Postdoctoral Fellow)
Dr. Horia Vais (Research Specialist)
Wint Thu Saung (Research Specialist)
Karthik Babu Mallilankaraman (Research Specialist)

Selected Publications

149. Tordoff, M.G., H. T. Ellis, T. R. Aleman, A. Downing, P. Marambaud, J. K. Foskett, R. M. Dana and S. A. McCaughey: Salty Taste Deficits in CALHM1 Knockout Mice. Chemical Senses. Oxford University Press, 39(5): 515-28, Jul 2014.

Lee, R. J. and J. K. Foskett: Ca(2+) signaling and fluid secretion by secretory cells of the airway epithelium. Cell Calcium 55(6): 325-36, Jun 2014.

Shilling, D., M. Müller, H. Takano, D-O. D. Mak, T. Abel, D. A. Coulter and J. K. Foskett. : Suppression of InsP3 receptor-mediated Ca2+ signaling alleviates mutant presenilin-linked familial Alzheimer's disease pathogenesis. Journal of Neuroscience 34(20): 6910-23, May 2014.

Joseph, J. D., Y. Peng, MD, D.-O. D. Mak, K.-H. Cheung, H. Vais, J. K. Foskett and H. Wei: General Anesthetic Isoflurane Modulates Inositol 1,4,5-Trisphosphate Receptor Calcium Channel Opening. Anesthesiology Page: E-Pub (ahead of print), 2014.

Taruno A, Matsumoto I, Ma Z, Marambaud P, Foskett JK.: How do taste cells lacking synapses mediate neurotransmission? CALHM1, a voltage-gated ATP channel. Bioessays 35(12): 1111-8, Dec 2013.

Sung PJ, Tsai FD, Vais H, Court H, Yang J, Fehrenbacher N, Foskett JK, Philips MR.: Phosphorylated K-Ras limits cell survival by blocking Bcl-xL sensitization of inositol trisphosphate receptors. Proceedings of the National Academy of Sciences of the United States of America 110(51): 20593-8, Dec 2013.

Mak DO, Vais H, Cheung KH, Foskett JK.: Nuclear patch-clamp electrophysiology of Ca2+ channels. Cold Spring Harbor Protocols. Cold Spring Harbor Laboratory Press, 9: 885-91, Sep 2013 Notes: Cover Article.

Mak D.O., H. Vais, K.H. Cheung and J.K. Foskett: Patch clamp electrophysiology of intracellular Ca2+ channels. Cold Spring Harbor Protocols. Cold Spring Harbor Laboratory Press, 9: 787-97, Sep 2013.

Mak D.O., H. Vais, K.H. Cheung and J.K. Foskett: Isolating nuclei from cultured cells for patch-clamp electrophysiology of intracellular Ca(2+) channels. Cold Spring Harbor Protocols. Cold Spring Harbor Laboratory Press, 9: 880-4, Sep 2013.

Mak DO, Vais H, Cheung KH, Foskett JK.: Patch-clamp electrophysiology of intracellular Ca2+ channels. Calcium Techniques. M. D. Bootman, D. I. Yule and G. B. Bultynck (eds.). Cold Spring Harbor Laboratory Press, 9: 787-97, Sep 2013.

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Last updated: 06/24/2014
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