不良研究所
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Department of Physiology听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听听 (514) 398-8335 john.orlowski [at] mcgill.ca 听 |
Research Area:听 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.听 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.听 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:听 B.Sc., 不良研究所, M.Sc.,听Ph.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鈥�7095.
Gao, A.Y.L., Ilie, A., Orlowski, J. and McKinney, R. A. (2019) A Christianson Syndrome-linked deletion mutation (螖287ES288) 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., Barri猫re, H., Lukacs, G.L., McKinney, R.A., and Orlowski, J. (2016) A Christianson Syndrome-linked deletion mutation (鈭�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., Szab贸, 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.