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Accordingly, PRRT2 loss-of-function mutations associate with pleiotropic paroxysmal neurological disorders, including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. PRRT2 is a negative modulator of the membrane exposure and biophysical properties of Na\n                    <jats:sup>+<\/jats:sup>\n                    channels Na\n                    <jats:sub>V<\/jats:sub>\n                    1.2\/Na\n                    <jats:sub>V<\/jats:sub>\n                    1.6 predominantly expressed in brain glutamatergic neurons. Na\n                    <jats:sub>V<\/jats:sub>\n                    channels form complexes with \u03b2-subunits that facilitate the membrane targeting and the activation of the \u03b1-subunits. The opposite effects of PRRT2 and \u03b2-subunits on Na\n                    <jats:sub>V<\/jats:sub>\n                    channels raises the question of whether PRRT2 and \u03b2-subunits interact or compete for common binding sites on the \u03b1-subunit, generating Na\n                    <jats:sup>+<\/jats:sup>\n                    channel complexes with distinct functional properties. Using a heterologous expression system, we have observed that \u03b2-subunits and PRRT2 do not interact with each other and act as independent non-competitive modulators of Na\n                    <jats:sub>V<\/jats:sub>\n                    1.2 channel trafficking and biophysical properties. PRRT2 antagonizes the \u03b24-induced increase in expression and functional activation of the transient and persistent Na\n                    <jats:sub>V<\/jats:sub>\n                    1.2 currents, without affecting resurgent current. The data indicate that \u03b24-subunit and PRRT2 form a push\u2013pull system that finely tunes the membrane expression and function of Na\n                    <jats:sub>V<\/jats:sub>\n                    channels and the intrinsic neuronal excitability.\n                  <\/jats:p>","DOI":"10.1007\/s12035-022-03112-x","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T07:06:20Z","timestamp":1669619180000},"page":"1281-1296","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["A Push\u2013Pull Mechanism Between PRRT2 and \u03b24-subunit Differentially Regulates Membrane Exposure and Biophysical Properties of NaV1.2 Sodium Channels"],"prefix":"10.1007","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6272-1821","authenticated-orcid":false,"given":"Pierluigi","family":"Valente","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Marte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Franchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Sterlini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Casagrande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Corradi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Baldelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0653-8368","authenticated-orcid":false,"given":"Fabio","family":"Benfenati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"key":"3112_CR1","doi-asserted-by":"publisher","first-page":"3476","DOI":"10.1093\/brain\/awv317","volume":"138","author":"D Ebrahimi-Fakhari","year":"2015","unstructured":"Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C (2015) The evolving spectrum of PRRT2-associated paroxysmal diseases. 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