Department of PhysiologyÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌý 91µÎµÎ Bellini Life Sciences Complex Room 166 3649 promenade Sir William Osler Montreal, QC H3G 0B1ÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌýÌý (514) 398-8335 john.orlowski [at] mcgill.ca Ìý

Research Area:Ìý Cell and Molecular Biology

Research Description:

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.Ìý 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.Ìý 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:Ìý B.Sc., 91µÎµÎ, M.Sc.,ÌýPh.D., Queen's

Recent Selected Publications:

Freeman, S.A., Grinstein, G. and Orlowski, J. (2023) Determinants, maintenance and function of organellar pH. Physiological Reviews 103(1): 515-606.

Dong, Y., Li, H., Ilie, A., Gao, Y., Boucher, A., Zhang, X.C., Orlowski, J. and Zhao, Y. (2022) Structural basis of autoinhibition of the human NHE3-CHP1 complex. Science Advances 8(21): eabn3925.

Dong, Y., Gao, Y., Ilie, A., Kim, D., Boucher, A., Li, B., Zhang, X.C., Orlowski, J. and Zhao, Y. (2021) Structure and mechanism of the human NHE1-CHP1 complex. Nature Communications 12(1): 3474

Petitjean H., Fatima T., Mouchbahani-Constance S., Davidova A., Ferland C.E., Orlowski J, Sharif-Naeini R. Loss of SLC9A6/NHE6 impairs nociception in a mouse model of Christianson Syndrome. Pain. 2020 Jun 15; [Epub ahead of print] PubMed PMID: 32569089.

Ilie A., Boucher A., Park J., Berghuis A.M., McKinney R.A., and Orlowski J. (2020) Assorted dysfunction of endosomal alkali cation/proton exchanger SLC9A6 variants linked to Christianson Syndrome. J. Biol. Chem. 295(20): 7075–7095.

Gao, A.Y.L., Ilie, A., Orlowski, J. and McKinney, R. A. (2019) A Christianson Syndrome-linked deletion mutation (Δ²⁸⁷ES²⁸⁸) in SLC9A6 impairs hippocampal neuronal plasticity. Neurobiol. Dis. 130: 104490

Ilie A., Gao A.Y.L., Boucher A., Park J., Berghuis A.M., Hoffer M.J.V., Hilhorst-Hofstee Y., McKinney R.A., and Orlowski J. (2019) A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome. Neurobiol. Dis. 121: 187-204.

Khayat W., Hackett A., Shaw M., Ilie A., Dudding-Byth T., Kalscheuer V.M., Christie L._, Corbett M.A., Juusola J., Friend K.L., Kirmse B.M., Gecz J., Field M. and Orlowski J. (2019) A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation. Hum. Mol. Genet. 28(4): 598-614.

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. Mol. Neurodegener. 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.

Casey, J. R., Grinstein, S. and Orlowski, J. (2010) Sensors and regulators of intracellular pH. Nature Reviews Molecular Cell Biology 11(1):50-61.