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The norepinephrine transporter (NET) modulates adrenergic homeostasis via the reuptake of extracellular catecholamines and is implicated in the pathogenesis of adrenergic and neurological disorders. In this study, we reveal NET is palmitoylated in male Sprague\u2013Dawley rats and Lilly Laboratory Cell Porcine Kidney (LLC\u2010PK\n                    <jats:sub>1<\/jats:sub>\n                    ) cells. S\u2010palmitoylation, or the addition of a 16\u2010carbon saturated fatty acid, is a reversible post\u2010translational modification responsible for the regulation of numerous biological mechanisms. We found that LLC\u2010PK\n                    <jats:sub>1<\/jats:sub>\n                    NET is dynamically palmitoylated, and that inhibition with the palmitoyl acyltransferase (DHHC) inhibitor, 2\u2010bromopalmitate (2BP) results in decreased NET palmitoylation within 90\u2009min of treatment. This result was followed closely by a reduction in transport capacity, cell surface, and total cellular NET expression after 120\u2009min of treatment. Increasing 2BP concentrations and treatment time revealed a nearly complete loss of total NET protein. Co\u2010expression with individual DHHCs revealed a single DHHC enzyme, DHHC1, promoted wild\u2010type (WT) hNET palmitoylation and elevated NET protein levels. The POTS\u2010associated NET mutant, A457P, exhibits dramatically decreased transport capacity and cell surface levels which we have confirmed in the current study. In an attempt to recover A457P NET expression, we co\u2010expressed the A457P variant with DHHC1 to drive expression as seen with the WT protein but instead saw an increase in NET N\u2010terminal immuno\u2010detectable forms and fragments. Elimination of a potential palmitoylation site at cysteine 44 in the N\u2010terminal tail of hNET resulted in a low expression phenotype mimicking the A457P hNET variant. Further investigation of A457P NET palmitoylation and surface expression is necessary, but our preliminary novel findings reveal palmitoylation as a mechanism of NET regulation and suggest that dysregulation of this process may contribute to the pathogenesis of adrenergic disorders like POTS.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc16241-fig-0011-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.16241","type":"journal-article","created":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T17:50:15Z","timestamp":1728755415000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Palmitoylation regulates norepinephrine transporter uptake, surface localization, and total expression with pathogenic implications in postural orthostatic tachycardia syndrome"],"prefix":"10.1111","volume":"169","author":[{"given":"Christopher R.","family":"Brown","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences University of North Dakota School of Medicine and Health Sciences  Grand Forks North Dakota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhur","family":"Shetty","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of North Dakota School of Medicine and Health Sciences  Grand Forks North Dakota 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