J. Kevin Foskett, PhD

faculty photo
Isaac Ott Professor of Physiology
Department: Physiology
Graduate Group Affiliations

Contact information
Department of Physiology
University of Pennsylvania
School of Medicine
700D Clinical Research Bldg./ 6085
Philadelphia, PA 19104
Office: (215) 898-1354
Education:
B.S.
Duke University, 1974.
M.S.
University of South Carolina, 1977.
Ph.D.
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 most broadly interested in the molecular biology and physiological mechanisms of solute transport and intracellular signaling, and the roles of these processes in disease. Specifically, we are working in the following research areas:

First, we study the molecular physiology of intracellular calcium (Ca2+) release ion channels, esp. the inositol trisphosphate receptor. Calcium release from intracellular storage compartments is a ubiquitous cell signaling mechanism that regulates processes as diverse as fertilization, gene transcription, secretion and learning and memory. The calcium signaling system is amazingly complex in both time and space. A major problem in understanding how this signaling system works is that the release channel is located inside cells. We have developed novel approaches to overcome this limitation. We employ a variety of biophysical, molecular and biochemical approaches to study the molecular physiology of the inositol trisphosphate receptor calcium channel, ranging from single molecule studies to optical imaging of calcium signals in individual cells.

Of primary interest now is the role of this channel in Ca2+ signaling to mitochondria, and how this impinges on cellular physiology and pathophysiology. Our foci now are on bioenergetics, programmed cell death, autophagy, Alzheimer's disease and cancer.

Another focus of the lab is the disease cystic fibrosis. CF is the most common lethal recessive genetic disease. It is caused by mutations in the gene product, named CFTR, which is a chloride ion channel that is expressed in the tissues affected in the disease, including lungs, pancreas, reproductive tract and intestines. Our focus now is on the submucosal glands in the lung,which play important roles in lung homeostasis and innate immune defense, and where CFTR is expressed at high levels. These glands are complex and composed of many cells types. We are using a combination of single cell gene expression profiling, electrophysiology and optical imaging to identify the function and role of each cell type in the gland. We have identified a signal transduction pathway that could be targeted therapeutically in CF.

A third focus in on a novel ion channel that we have discovered. The channel is part of a larger family of proteins whose functions are unknown. The channel we have identified in involved in neuronal excitability and sweet and bitter taste perception in taste buds. Our focus now is to understand the biophysical properties of this new ion channel, and to determine how it functions as an essential mediator of taste perception.

The techniques we employ span the spectrum from biophysical to molecular, reflecting our approach as cell physiologists. Biochemical and molecular tools are used within the context of physiological measurement. Our goal is to understand how molecular behavior results in complex cell physiological processes, including those involved in signal transduction and epithelial and nerve cell functions. We employ:

- electrophysiology, including nuclear envelope patch clamping, two-electrode voltage clamp of oocytes and single channel and whole-cell recording from mammalian cells;
- confocal imaging microscopy of single living cells
- microinjection
- yeast 2-hybrid system
- expression studies
- molecular biology
- biochemistry
-histochemistry

Lab personnel (11/1/12):
Dr. Daniel Mak, PhD (Research Investigator)
Dustin Shilling (Neuroscience Graduate Student)
Dr. Horia Vais (Research Specialist)
Dr. Zhongming Ma (Research Investigator)
Dr. Akiyuki Taruno (Postdoctoral Fellow)

Selected Publications

Siebert Adam P, Ma Zhongming, Grevet Jeremy D, Demuro Angelo, Parker Ian, Foskett J Kevin: Structural and Functional Similarities of Calcium Homeostasis Modulator 1 (CALHM1) Ion Channel With Connexins, Pannexins and Innexins. The Journal of biological chemistry Jan 2013.

Mallilankaraman Karthik, Cárdenas César, Doonan Patrick J, Chandramoorthy Harish C, Irrinki Krishna M, Golenár Tünde, Csordás György, Madireddi Priyanka, Yang Jun, Müller Marioly, Miller Russell, Kolesar Jill E, Molgó Jordi, Kaufman Brett, Hajnóczky György, Foskett J Kevin, Madesh Muniswamy: MCUR1 is an essential component of mitochondrial Ca(2+) uptake that regulates cellular metabolism. Nature cell biology 14(12): 1336-43, Dec 2012.

Vais Horia, Foskett J Kevin, Ullah Ghanim, Pearson John E, Daniel Mak Don-On: Permeant calcium ion feed-through regulation of single inositol 1,4,5-trisphosphate receptor channel gating. The Journal of general physiology 140(6): 697-716, Dec 2012.

Mallilankaraman Karthik, Doonan Patrick, Cárdenas César, Chandramoorthy Harish C, Müller Marioly, Miller Russell, Hoffman Nicholas E, Gandhirajan Rajesh Kumar, Molgó Jordi, Birnbaum Morris J, Rothberg Brad S, Mak Don-On Daniel, Foskett J Kevin, Madesh Muniswamy: MICU1 Is an Essential Gatekeeper for MCU-Mediated Mitochondrial Ca(2+) Uptake that Regulates Cell Survival. Cell 151(3): 630-44, Oct 2012.

Kopil Catherine M, Siebert Adam P, Foskett J Kevin, Neumar Robert W: Calpain-cleaved type 1 inositol 1,4,5-trisphosphate receptor impairs ER Ca(2+) buffering and causes neurodegeneration in primary cortical neurons. Journal of neurochemistry 123(1): 147-58, Oct 2012.

Lee Robert J, Foskett J Kevin: Why Mouse Airway Submucosal Gland Serous Cells Do Not Secrete Fluid in Response to cAMP Stimulation. The Journal of biological chemistry Sep 2012.

King J Darwin, Lee Jeffrey, Riemen Claudia E, Neumann Dietbert, Xiong Sheng, Foskett J Kevin, Mehta Anil, Muimo Richmond, Hallows Kenneth R: Role of Binding and Nucleoside Diphosphate Kinase A in the Regulation of the Cystic Fibrosis Transmembrane Conductance Regulator by AMP-activated Protein Kinase. The Journal of biological chemistry 287(40): 33389-400, Sep 2012.

Ma Zhongming, Siebert Adam P, Cheung King-Ho, Lee Robert J, Johnson Brian, Cohen Akiva S, Vingtdeux Valérie, Marambaud Philippe, Foskett J Kevin: Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability. Proceedings of the National Academy of Sciences of the United States of America 109(28): E1963-71, Jul 2012.

Shilling Dustin, Mak Don-On Daniel, Kang David E, Foskett J Kevin: Lack of evidence for presenilins as endoplasmic reticulum Ca2+ leak channels. The Journal of biological chemistry 287(14): 10933-44, Mar 2012.

Vais Horia, Foskett J Kevin, Mak Don-On Daniel: InsP3R channel gating altered by clustering? Nature 478(7368): E1-2; discussion E2-3, Oct 2011.

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Last updated: 03/25/2014
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