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PHT1 is an H+-coupled\/histidine symporter that can transport a wide range of oligopeptides, including a variety of bacterial-derived peptides. Moreover, it enables the scaffolding of various metabolic signaling molecules and interacts with key regulatory elements of the immune response. Not surprisingly, PHT1 has been implicated in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Unfortunately, the pharmacological development of PHT1 modulators has been hampered by the lack of suitable transport assays. To address this shortcoming, a novel transport assay based on solid-supported membrane-based electrophysiology (SSME) is presented. Key findings of the present SSME studies include the first recordings of electrophysiological properties, a pH dependence analysis, an assessment of PHT1 substrate selectivity, as well as the transport kinetics of the identified substrates. In contrast to previous work, PHT1 is studied in its native lysosomal environment. Moreover, observed substrate selectivity is validated by molecular docking. Overall, this new SSME-based assay is expected to contribute to unlocking the pharmacological potential of PHT1 and to deepen the understanding of its functional properties.<\/jats:p>","DOI":"10.3390\/biom14070771","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T08:31:36Z","timestamp":1719563496000},"page":"771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Functional Characterization of the Lysosomal Peptide\/Histidine Transporter PHT1 (SLC15A4) by Solid Supported Membrane Electrophysiology (SSME)"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9951-1390","authenticated-orcid":false,"given":"Jonai","family":"Pujol-Gim\u00e9nez","sequence":"first","affiliation":[{"name":"Department of Nephrology and Hypertension, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"},{"name":"Department of Biomedical Research, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven P.","family":"Baumann","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"},{"name":"Department of Biomedical Research, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1608-2234","authenticated-orcid":false,"given":"Tin Manh","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"},{"name":"Department of Biomedical Research, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartlomiej","family":"Augustynek","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"},{"name":"Department of Biomedical Research, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias A.","family":"Hediger","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Hypertension, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"},{"name":"Department of Biomedical Research, Inselspital, University of Bern, Kinderklinik, Freiburgstrasse 15, 3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.mam.2012.11.003","article-title":"Proton-coupled oligopeptide transporter family SLC15: Physiological, pharmacological and pathological implications","volume":"34","author":"Smith","year":"2013","journal-title":"Mol. 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