{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T19:21:45Z","timestamp":1787858505909,"version":"build-2784847793"},"reference-count":122,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T00:00:00Z","timestamp":1759708800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["IJMS"],"abstract":"<jats:p>Two-pore channel 2 (TPC2) is a member of the endolysosomal ion channel family, playing critical roles in intracellular calcium signaling and endomembrane dynamics. This review provides an in-depth analysis of TPC2, covering its structural and functional properties, physiological roles, and involvement in human diseases. We discuss current experimental approaches to studying TPC2, including heterologous expression in plant vacuoles and computational modeling strategies. Particular emphasis is placed on the structural determinants of ion permeation, with a focus on the selectivity filter and the central cavity\u2019s influence on channel kinetics. Furthermore, we explore emerging roles of TPC2 in viral infections, particularly SARS-CoV-2, and in cancer, including melanoma progression and neoangiogenesis. The inhibitory potential of natural compounds, such as naringenin, is also examined. By offering a comprehensive overview of current knowledge and methodologies, this review underscores the potential of TPC2 as a promising pharmacological target in both infectious and neoplastic diseases.<\/jats:p>","DOI":"10.3390\/ijms26199708","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:05:06Z","timestamp":1759763106000},"page":"9708","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The Two-Pore Channel 2 in Human Physiology and Diseases: Functional Characterisation and Pharmacology"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-3720","authenticated-orcid":false,"given":"Laura","family":"Lagostena","sequence":"first","affiliation":[{"name":"Institute of Biophysics, National Research Council, Via De Marini 6, 16149 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9851-9932","authenticated-orcid":false,"given":"Velia","family":"Minicozzi","sequence":"additional","affiliation":[{"name":"INFN and Department of Physics, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Meucci","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, SAPIENZA University of Rome, 16 Via A. Scarpa, 00161 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4401-9913","authenticated-orcid":false,"given":"Antonella","family":"Gradogna","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, National Research Council, Via De Marini 6, 16149 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Milenkovic","sequence":"additional","affiliation":[{"name":"Department of Physics, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fioretta","family":"Palombi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, SAPIENZA University of Rome, 16 Via A. Scarpa, 00161 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4272-902X","authenticated-orcid":false,"given":"Matteo","family":"Ceccarelli","sequence":"additional","affiliation":[{"name":"Department of Physics, University of Cagliari, 09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8453-287X","authenticated-orcid":false,"given":"Antonio","family":"Filippini","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology, Forensic Medicine and Orthopaedics, Unit of Histology and Medical Embryology, SAPIENZA University of Rome, 16 Via A. Scarpa, 00161 Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5060-3657","authenticated-orcid":false,"given":"Armando","family":"Carpaneto","sequence":"additional","affiliation":[{"name":"Institute of Biophysics, National Research Council, Via De Marini 6, 16149 Genova, Italy"},{"name":"Department of Earth, Environment and Life Sciences (DISTAV), University of Genoa, Viale Benedetto XV 5, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/329833a0","article-title":"Cytoplasmic Calcium Regulates Voltage-Dependent Ion Channels in Plant Vacuoles","volume":"329","author":"Hedrich","year":"1987","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s004250100519","article-title":"Effects of Cytoplasmic Mg2+ on Slowly Activating Channels in Isolated Vacuoles of Beta Vulgaris","volume":"213","author":"Carpaneto","year":"2001","journal-title":"Planta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bpc.2018.02.006","article-title":"Modulation of Calcium and Potassium Permeation in Plant TPC Channels","volume":"236","author":"Carpaneto","year":"2018","journal-title":"Biophys. 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