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We provide evidence that chromaffin cell malfunction derives from altered Cav1.2 channel gating.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>L\u2010type voltage\u2010gated calcium (Cav1) channels have a key role in long\u2010term synaptic plasticity, sensory transduction, muscle contraction and hormone release. A point mutation in the gene encoding Cav1.2 (<jats:italic>CACNA1C<\/jats:italic>) causes Tymothy syndrome (TS), a multisystem disorder featuring cardiac arrhythmias, autism spectrum disorder (ASD) and adrenal gland dysfunction. In the more severe type\u20102 form (TS2), the missense mutation G406R is on exon 8 coding for the IS6\u2010helix of the Cav1.2 channel. The mutation causes reduced inactivation and induces autism. How this occurs and how Cav1.2 gating\u2010changes alter cell excitability, neuronal firing and hormone release on a molecular basis is still largely unknown. Here, using the TS2\u2010neo mouse model of TS we show that the G406R mutation altered excitability and reduced secretory activity in adrenal chromaffin cells (CCs). Specifically, the TS2 mutation reduced the rate of voltage\u2010dependent inactivation and shifted leftward the activation and steady\u2010state inactivation of L\u2010type channels. This markedly increased the resting \u2018window\u2019 Ca<jats:sup>2+<\/jats:sup> current that caused an increased percentage of CCs undergoing abnormal action potential (AP) burst firing, cell swelling, reduced mitochondrial metabolism and decreased catecholamine release. The increased \u2018window\u2019 Ca<jats:sup>2+<\/jats:sup> current caused also decreased Na<jats:sub>V<\/jats:sub> channel density and increased steady\u2010state inactivation, which contributed to the increased abnormal burst firing. Overnight incubation with the L\u2010type channel blocker nifedipine rescued the normal AP firing of CCs, the density of functioning Na<jats:sub>V<\/jats:sub> channels and their steady\u2010state inactivation. We provide evidence that CC malfunction derives from the altered Cav1.2 channel gating and that dihydropyridines are potential therapeutics for ASD.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp277487","type":"journal-article","created":{"date-parts":[[2019,1,10]],"date-time":"2019-01-10T17:34:19Z","timestamp":1547141659000},"page":"1705-1733","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Impaired chromaffin cell excitability and exocytosis in autistic Timothy syndrome TS2\u2010neo mouse rescued by L\u2010type calcium channel blockers"],"prefix":"10.1113","volume":"597","author":[{"given":"Chiara","family":"Calorio","sequence":"first","affiliation":[{"name":"Department of Drug Science, NIS Centre University of Torino  Torino Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Gavello","sequence":"additional","affiliation":[{"name":"Department of Drug Science, NIS Centre 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