|Department of Physiology
McIntyre Medical Sciences Building
3655 Promenade Sir William Osler
Montréal, Québec H3G 1Y6
john.orlowski [at] mcgill.ca
Laboratory Web Site:
Research Area: Cell and Molecular Biology
The scientific interests of my laboratory are directed towards developing a comprehensive understanding of the dynamics of cellular acid-base (pH) homeostasis as it pertains to human health and disease, with a focus on one major component of the cellular pH-regulatory machinery, namely alkali cation [Na+, K+, Li+]/proton (H+) exchangers, commonly referred to as Na+/H+ exchangers (NHEs) (i.e., members of the solute carrier SLC9 gene family). These transporters play direct roles in controlling not only cellular pH and volume, but also contribute to a host of other physiological processes such as cellular adhesion, migration, proliferation, transformation and apoptosis. Disruptions in the normal function of certain NHEs have been linked to the progression of a number of human diseases, including hypertension, cardiac arrhythmias and failure, stroke, congenital secretory diarrhea, diabetes, and certain neurological disorders (e.g., Lichtenstein-Knorr Syndrome, Christianson Syndrome, epilepsy, autism, attention deficit hyperactivity disorder).
Previous work by my laboratory resulted in the identification and molecular cloning of several novel members of the mammalian NHE/SLC9 gene family. My current research uses a range of molecular, cellular and physiological techniques to address several distinct aspects of NHE biology, including the following aims: (1) to define the transmembrane organization and structural domains of the exchanger responsible for cation translocation and drug recognition in order to develop a molecular model that accounts for the functional dynamics of this transporter; (2) to define the protein sorting and signalling mechanisms that underlie the membrane targeting and regulation of the NHEs; (3) to evaluate the physiological and pathophysiological contributions of certain NHEs to cell function, health and disease.
Education: B.Sc., McGill, M.Sc., Ph.D., Queen's
Ilie, A., Gao, A.Y.L., Reid, J., Boucher, A., McEwan, C., Barrière, H., Lukacs, G.L., McKinney, R.A., and Orlowski, J. (2016) A Christianson Syndrome-linked deletion mutation (∆287ES288) in SLC9A6 disrupts recycling endosomal function and elicits neurodegeneration and cell death. Molecular Neurodegeneration 11:63.
Jinadasa, T., Josephson, C.B., Boucher, A. and Orlowski, J. (2015) Determinants of cation permeation and drug sensitivity in predicted transmembrane helix 9 and adjoining exofacial re-entrant loop 5 of Na+/H+ exchanger NHE1. J. Biol. Chem.: 290(29):18173-18186.
Jinadasa, T., Szabó, E.Z., Numata, M., and Orlowski, J. (2014) Activation of AMP-activated protein kinase regulates hippocampal neuronal pH by recruiting Na+/H+ exchanger NHE5 to the cell surface. J. Biol. Chem. 289(30): 20879-20897.
Ilie, A., Weinstein, E., Boucher, A., McKinney, R.A. and Orlowski, J. (2014) Impaired posttranslational processing and trafficking of an endosomal Na+/H+ exchanger NHE6 mutant (D370WST372) associated with X-Linked intellectual disability and autism. Neurochem. Intl. 73:192-203.
Liu, Y., Zaun, H.C., Orlowski, J. and Ackerman, S.L. (2013) CHP1-mediated NHE1 biosynthetic maturation is required for Purkinje cell axon homeostasis. J. Neurosci. 33(31): 12656-12669.
Deane, E.C., Ilie, A.E., Sizdahkhani, S., Das Gupta, M., Orlowski, J. and McKinney, R.A. (2013) Enhanced recruitment of endosomal Na+/H+ exchanger NHE6 into dendritic spines of hippocampal pyramidal neurons during NMDA receptor-dependent long-term potentiation. J. Neurosci. 33: 595-610.
Lukashova, V., Jinadasa, T., Ilie, A.E., Verbich, D., Cooper E. and Orlowski, J. (2013) The Na+/H+ exchanger NHE5 isoform is sorted to discrete intracellular vesicles in the central and peripheral nervous systems. Adv. Exp. Med. Biol. 961: 397-410.
Zaun, H. C., Shrier, A., and Orlowski, J. (2012) N-myristoylation and Ca2+-binding of calcineurin B-homologous protein CHP3 are required to enhance Na+/H+ Exchanger NHE1 half-life and activity at the plasma membrane. J. Biol. Chem. 287(44):36883-95.
Lukashova, V., Szabó, E.Z., Jinadasa, T., Mokhov, A., Litchfield, D.W. and Orlowski, J. (2011) CK2 Phosphorylation of an acidic Ser/Thr di-isoleucine motif in Na+/H+ exchanger NHE5 promotes association with β-arrestin2 and endocytosis. J. Biol. Chem. 286(13):11456-11468.
Alexander, R.T., Yeung, T., Furuya, W., Peltekova, I., Boucher, A., Zasloff, M., Orlowski, J. and Grinstein, S. (2011) Membrane surface charge dictates the structure and function of the epithelial Na+/H+ exchanger. EMBO J. 30(4):679-691.
Casey, J.R., Grinstein, S. and Orlowski, J. (2010) Sensors and regulators of intracellular pH. Nature Reviews Molecular Cell Biology 11(1):50-61.
Kintner, D.B., Chen, X., Currie, J., Chanana, V., Ferrazzano, P., Chiu, S.-Y. , Baba, A., Matsuda, M., Cohen, M., Orlowski, J., Taunton, J., and Sun, D. (2010) Excessive Na+/H+ exchange in disruption of dendritic Na+ and Ca2+ homeostasis and mitochondrial dysfunction following in vitro ischemia. J. Biol. Chem. 285(45): 35155–35168.
Zaun, H.C., Shrier, A. and Orlowski, J. (2008) Calcineurin B-homologous protein 3 promotes the biosynthetic maturation, cell surface stability and optimal transport of the Na+/H+ exchanger NHE1 isoform. J. Biol. Chem. 283(18):12456-67.
Alexander, R.T., Furuya, W., Szaszi, K., Orlowski, J., and Grinstein, S. (2005) Rho GTPases dictate the mobility of the Na+/H+ exchanger NHE3 in epithelia. Role in apical retention and targeting. Proc. Natl. Acad. Sci. USA 102(34): 12253-12258.
Lin, P. J. C., Williams, W. P., Luu, Y., Molday, R. S., Orlowski, J. and Numata, M. (2005) Secretory carrier membrane proteins interact and regulate trafficking of the organellar (Na+, K+)/H+ exchanger NHE7. J. Cell Sci. 118: 1885-1897.
Szabó, E.Z., Numata, M., Lukashova, V., Iannuzzi, P. and Orlowski, J. (2005) β-Arrestins bind and decrease cell-surface abundance of the Na+/H+ exchanger NHE5 isoform. Proc. Natl. Acad. Sci. USA 102(8): 2790-2795.