{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:18:03Z","timestamp":1792163883644,"version":"4.4.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"9","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,3,4]]},"abstract":"<jats:p>\n                    The mechanism of action of the antiepileptic and antinociceptive drugs of the gabapentinoid family has remained poorly understood. Gabapentin (GBP) binds to an exofacial epitope of the \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4-1 and \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4-2 auxiliary subunits of voltage-gated calcium channels, but acute inhibition of calcium currents by GBP is either very minor or absent. We formulated the hypothesis that GBP impairs the ability of \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4 subunits to enhance voltage-gated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel plasma membrane density by means of an effect on trafficking. Our results conclusively demonstrate that GBP inhibits calcium currents, mimicking a lack of \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4 only when applied chronically, but not acutely, both in heterologous expression systems and in dorsal root-ganglion neurons. GBP acts primarily at an intracellular location, requiring uptake, because the effect of chronically applied GBP is blocked by an inhibitor of the system-L neutral amino acid transporters and enhanced by coexpression of a transporter. However, it is mediated by \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4 subunits, being prevented by mutations in either \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4-1 or \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4-2 that abolish GBP binding, and is not observed for \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4-3, which does not bind GBP. Furthermore, the trafficking of \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4-2 and Ca\n                    <jats:sub>V<\/jats:sub>\n                    2 channels is disrupted both by GBP and by the mutation in \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4-2, which prevents GBP binding, and we find that GBP reduces cell-surface expression of \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4-2 and Ca\n                    <jats:sub>V<\/jats:sub>\n                    2.1 subunits. Our evidence indicates that GBP may act chronically by displacing an endogenous ligand that is normally a positive modulator of \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4 subunit function, thereby impairing the trafficking function of the \u03b1\n                    <jats:sub>2<\/jats:sub>\n                    \u03b4 subunits to which it binds.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0708930105","type":"journal-article","created":{"date-parts":[[2008,2,25]],"date-time":"2008-02-25T21:27:45Z","timestamp":1203974865000},"page":"3628-3633","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":370,"title":["Pharmacological disruption of calcium channel trafficking by the \u03b1\n                    <sub>2<\/sub>\n                    \u03b4 ligand gabapentin"],"prefix":"10.1073","volume":"105","author":[{"given":"Jan","family":"Hendrich","sequence":"first","affiliation":[{"name":"*Laboratory for Cellular and Molecular Neuroscience, Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra Tran","family":"Van Minh","sequence":"additional","affiliation":[{"name":"*Laboratory for Cellular and Molecular Neuroscience, Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fay","family":"Heblich","sequence":"additional","affiliation":[{"name":"*Laboratory for Cellular and Molecular Neuroscience, Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Nieto-Rostro","sequence":"additional","affiliation":[{"name":"*Laboratory for Cellular and Molecular Neuroscience, Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Watschinger","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazie, Abteilung f\u00fcr Pharmakologie und Toxikologie, Universit\u00e4t Innsbruck, A-6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Striessnig","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmazie, Abteilung f\u00fcr Pharmakologie und Toxikologie, Universit\u00e4t Innsbruck, A-6020 Innsbruck, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack","family":"Wratten","sequence":"additional","affiliation":[{"name":"*Laboratory for Cellular and Molecular Neuroscience, Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Davies","sequence":"additional","affiliation":[{"name":"*Laboratory for 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