Larry Fliegel

Larry Fliegel


Ph.D, University of Calgary

Office: 780-492-1848
Lab: 780-492-1847
Fax: 780-492-0886


Handling acid is a problem in all organisms. As a result of metabolism, excess intracellular acid is produced in all cells. Too much acid has a deleterious effect on the activity of various enzymes and results in abnormalities in metabolism and cell cycle. In the heart, too much acid inhibits contractile activity and damages the myocardium. Our laboratory studies the regulation of intracellular pH and the removal of excess intracellular acid. In mammalian tissues the main protein responsible for this is the Na+/H+ exchanger. The Na+/H+ exchanger is a mammalian plasma membrane protein that exchanges one intracellular proton for an extracellular sodium. It is involved in pH regulation and is stimulated by growth factors. Several isoforms of the protein exist (NHE1 to NHE10). NHE1 is the most widespread and exists in all mammalian cells. My laboratory has studied many aspects of the NHE1 protein. We have examined the structure and characterized activity of the protein. We have used site-specific mutagenesis to discover which amino acids are important in transport and have examined the structure of parts of the cytosolic and membrane domains. In collaboration with others we have elucidated the structure of parts of the membrane domain of the protein. My laboratory has also studied phosphorylation of the antiporter and factors affecting localization and targeting of the protein.

We have a special interest in the Na+/H+ exchanger in humans in disease. In the mammalian heart, because the protein is important in heart disease. In the heart we have examined regulation of expression and activity of the protein. We have shown that MAP kinase dependent pathways are key to the regulation of activity of the Na+/H+ exchanger. Both p90rsk and MAP kinase are key protein kinases involved in regulation of activity of the protein. The NHE1 protein is also critically involved breast cancer cells. 'Hyperactivation" of the protein acidifies the extracellular environment, promoting cell metastasis. We have shown that it is a key factor in metastasis of breast cancer cells and are working on both deducing the aberrant mechanisms involved and on treatments to prevent metastasis of breast cancer cells.
We also have an interest in ion movements in yeast. In Schizosaccharomyces pombe the Na+/H+ exchanger (sod2) moves Na+ out of the cell in exchange for H+. This protein functions in osmotolerance in yeast and plants. We have examined amino acids important in cation binding and transport in this protein.
Overall, our long-term goal is to understand how ions and coordinated and transported in membrane proteins and their regulation in the healthy and disease state. Many new projects are underway. We are always interested in recruiting high quality personnel so please contact me if you are interested in this area.


Selected Publications:

Fructose, Another Sweet for Cancer: A Context Acting Nutrient Hypothesis
Koltai T, Fliegel L.
Gene Expression (2023) 22(2):141-155.

Structure and Function of Membrane Proteins
Fliegel L.
Int J Mol Sci (2023) Vol. 24, Issue 9.

pH deregulation as the eleventh hallmark of cancer
Koltai T, Fliegel L, Reshkin SJ, Baltazar F, Cardone RA, Alfarouk KO, Afonso J.
Elsevier publishers (2023) ISBN: 9780443154614

The Remaining Conundrum of the Role of the Na+/H+ Exchanger Isoform 1 (NHE1) in Cardiac Physiology and Pathology: Can It Be Rectified?
Karmazyn M, Pierce GN, Fliegel L.
Rev. Cardiovasc. Med. (2022) 23(8), 284

Acute SGLT-2i treatment improves cardiac efficiency during myocardial ischemia independent of Na+/H+ exchanger-1
Baker HE, Tune JD, Mather KJ, Blaettner BS, Clark HE, Li F, Li X, Kowala MC, Fliegel L, Goodwill AG.
International Journal of Cardiology. (2022) 363:138-148

Permissive role of Na+/H+ exchanger isoform 1 in migration and invasion of triple-negative basal-like breast cancer cells
Li X, Fliegel L.
Molecular and Cellular Biochemistry. (2022) 477 (4):1207-1261.

Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions
Koltai T, Fliegel L.
Journal of Evidence-Based Integrative Medicine. (2022) 27:1-38

Amino Acids 785, 787 of the Na+/H+ Exchanger Cytoplasmic Tail Modulate Protein Activity and Tail Conformation
Li X, Tu T, Quan S, Quintero FJ, Fahlman R, Fliegel L.
IJMS. (2021) 22 (21)

Roles of the Na+/H+ Exchanger Isoform 1 and Urokinase in Prostate Cancer Cell Migration and Invasion
Li X, Buckley B, Stoletov K, Jing Y, Ranson M, Lewis JD, Kelso M, Fliegel L.
IJMS. (2021) 22, 11349.

Prostate Cancer Metabolism. From Biochemistry to Therapeutics
Koltai T, Reshkin SJ, Baltazar F,  Fliegel L.
Elsevier Publishers, Academic Press (2021) Paperback ISBN: 9780323905282.

Characterization of modeled inhibitory binding sites on isoform one of the Na+/H+ exchanger
Li X, Kim J, Yang J, Dutta D,  Fliegel L.
BBA Biomembranes. (2021) 1863(9):183648

Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors
Buckley BJ, Kumar A, Aboelela A, Bujaroski RS, Li X, Majed H,  Fliegel L, Ranson M, Kelso MJ
Int J. Mol Sci. (2021) 22(6)

Expression and detergent free purification and reconstitution of the plant plasma membrane Na + /H + antiporter SOS1 overexpressed in Pichia pastoris
Dutta D, Esmaili M, Overduin M, Fliegel L.
BBA Biomembranes (2020) 1862(3):18311.

Mutation of SLC9A1, encoding the major Na+/H+ exchanger, causes ataxia-deafness Lichtenstein Knorr syndrome.
Guissart C, Li X, Leheup B, Drouot N, Montaut-Verient B, Raffo E, Jonveaux P, Roux AF, Claustres M, Fliegel L, Koenig M.
Hum Mol Genet. (2015) Jan 15;24(2):463-70.


Lab Members

Research Associates
Asad Ullah
Xiu Ju Li


Selected Publications


Lab Website


Office: 345a MSB

Lab: 345 MSB

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