{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:36:36Z","timestamp":1785411396038,"version":"3.56.0"},"reference-count":70,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MICIU","award":["PID2021-128133NB-I00\/AEI\/FEDER10.13039\/501100011033"],"award-info":[{"award-number":["PID2021-128133NB-I00\/AEI\/FEDER10.13039\/501100011033"]}]},{"DOI":"10.13039\/100012818","name":"Comunidad de Madrid","doi-asserted-by":"crossref","award":["PIPF-2022\/SAL-GL-25948"],"award-info":[{"award-number":["PIPF-2022\/SAL-GL-25948"]}],"id":[{"id":"10.13039\/100012818","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PIPF-2022\/SAL-GL-25948"],"award-info":[{"award-number":["PIPF-2022\/SAL-GL-25948"]}],"id":[{"id":"https:\/\/ror.org\/040scgh75","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Copper (Cu2+) is an essential trace element that participates as a cofactor in key metabolic enzymes such as cytochrome c oxidase and superoxide dismutase. However, excessive copper exposure can be toxic and disturbances in copper homeostasis have been associated with neurodegenerative diseases including Alzheimer\u2019s and Parkinson\u2019s disease. Despite growing evidence linking copper to neuronal dysfunction, the cellular mechanisms by which Cu2+ affects neuronal excitability and neurotransmission remain poorly understood. The aim of this study was to investigate the effects of acute Cu2+ exposure on ionic currents involved in cellular excitability and neurotransmitter release in bovine chromaffin cells. Methods: Primary cultures of bovine chromaffin cells were used as a neuroendocrine model to study cellular excitability. Voltage-dependent ionic currents were recorded using the whole-cell patch-clamp technique in voltage-clamp configuration. Catecholamine secretion was monitored by amperometry, and cytosolic Ca2+ dynamics were measured in fluo-4-loaded cells during depolarization induced by high K+ stimulation. Results: Acute Cu2+ exposure produced a concentration-dependent enhancement of depolarization-evoked catecholamine release. In parallel, Cu2+ inhibited voltage-dependent calcium (ICa), sodium (INa), potassium (IKv), and calcium\/voltage-dependent potassium (IKCa-v) currents in a concentration-dependent and partially reversible manner. In addition, Cu2+ increased basal cytosolic Ca2+ levels while reducing the amplitude of depolarization-evoked Ca2+ transients. Conclusions: Acute Cu2+ exposure exerts a dual effect in bovine chromaffin cells, inhibiting the ionic currents that support cellular excitability while potentiating catecholamine secretion. This apparent paradox is consistent with a disruption of intracellular Ca2+ homeostasis, in which elevated basal cytosolic Ca2+ may facilitate exocytosis despite reduced depolarization-evoked Ca2+ entry. These findings provide new insight into the mechanisms by which copper may alter neuronal signaling and contribute to neurotoxicity.<\/jats:p>","DOI":"10.3390\/ph19050716","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T10:15:27Z","timestamp":1777630527000},"page":"716","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Copper (Cu2+) Inhibits Voltage-Dependent Ionic Currents While Enhancing Neurotransmitter Release in Bovine Chromaffin Cells"],"prefix":"10.3390","volume":"19","author":[{"given":"V\u00edctor","family":"Varea-Tierno","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3088-5578","authenticated-orcid":false,"given":"Victoria Jim\u00e9nez","family":"Carretero","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1336-303X","authenticated-orcid":false,"given":"Minerva Reyes","family":"Almod\u00f3var","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Hern\u00e1ndez Campano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Arribas","family":"Tejedor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6628-6097","authenticated-orcid":false,"given":"Ricardo","family":"de Pascual","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7011-5351","authenticated-orcid":false,"given":"Jes\u00fas M.","family":"Hern\u00e1ndez-Guijo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Facultad de Medicina, Universidad Aut\u00f3noma de Madrid, Av. Arzobispo Morcillo 4, 28029 Madrid, Spain"},{"name":"Ram\u00f3n y Cajal Institute for Health Research, IRYCIS, Hospital Ram\u00f3n y Cajal, Ctra. de Colmenar Viejo, 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/978-94-007-7500-8_11","article-title":"Copper: Effects of Deficiency and Overload","volume":"Volume 13","author":"Scheiber","year":"2013","journal-title":"Interrelations Between Essential Metal Ions and Human Diseases"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1002\/prot.22783","article-title":"Similarity of Cytochrome c Oxidases in Different Organisms","volume":"78","author":"Popovic","year":"2010","journal-title":"Proteins"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.bbapap.2009.11.004","article-title":"The Structural Biochemistry of the Superoxide Dismutases","volume":"1804","author":"Perry","year":"2010","journal-title":"Biochim. 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