{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:22:39Z","timestamp":1790713359579,"version":"4.1.0"},"reference-count":70,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,1,26]],"date-time":"2015-01-26T00:00:00Z","timestamp":1422230400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2015,2,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\"><jats:list-item><jats:p>Mouse chromaffin cells (MCCs) of the adrenal medulla possess fast\u2010inactivating Nav channels whose availability alters spontaneous action potential firing patterns and the Ca<jats:sup>2+<\/jats:sup>\u2010dependent secretion of catecholamines.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Here, we report MCCs expressing large densities of neuronal fast\u2010inactivating Nav1.3 and Nav1.7 channels that carry little or no subthreshold pacemaker currents and can be slowly inactivated by 50% upon slight membrane depolarization.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Reducing Nav1.3\/Nav1.7 availability by tetrodotoxin or by sustained depolarization near rest leads to a switch from tonic to burst\u2010firing patterns that give rise to elevated Ca<jats:sup>2+<\/jats:sup>\u2010influx and increased catecholamine release.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Spontaneous burst firing is also evident in a small percentage of control MCCs.<\/jats:p><\/jats:list-item><jats:list-item><jats:p>Our results establish that burst firing comprises an intrinsic firing mode of MCCs that boosts their output. This occurs particularly when Nav channel availability is reduced by sustained splanchnic nerve stimulation or prolonged cell depolarizations induced by acidosis, hyperkalaemia and increased muscarine levels.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Action potential (AP) firing in mouse chromaffin cells (MCCs) is mainly sustained by Cav1.3 L\u2010type channels that drive BK and SK currents and regulate the pacemaking cycle. As secretory units, CCs optimally recruit Ca<jats:sup>2+<\/jats:sup>channels when stimulated, a process potentially dependent on the modulation of the AP waveform. Our previous work has shown that a critical determinant of AP shape is voltage\u2010gated sodium channel (Nav) channel availability. Here, we studied the contribution of Nav channels to firing patterns and AP shapes at rest (\u221250\u00a0mV) and upon stimulation (\u221240\u00a0mV). Using quantitative RT\u2010PCR and immunoblotting, we show that MCCs mainly express tetrodotoxin (TTX)\u2010sensitive, fast\u2010inactivating Nav1.3 and Nav1.7 channels that carry little or no Na<jats:sup>+<\/jats:sup>current during slow ramp depolarizations. Time constants and the percentage of recovery from fast inactivation and slow entry into closed\u2010state inactivation are similar to that of brain Nav1.3 and Nav1.7 channels. The fraction of available Nav channels is reduced by half after 10\u00a0mV depolarization from \u221250 to \u221240\u00a0mV. This leads to low amplitude spikes and a reduction in repolarizing K<jats:sup>+<\/jats:sup>currents inverting the net current from outward to inward during the after\u2010hyperpolarization. When Nav channel availability is reduced by up to 20% of total, either by TTX block or steady depolarization, a switch from tonic to burst firing is observed. The spontaneous occurrence of high frequency bursts is rare under control conditions (14% of cells) but leads to major Ca<jats:sup>2+<\/jats:sup>\u2010entry and increased catecholamine release. Thus, Nav1.3\/Nav1.7 channel availability sets the AP shape, burst\u2010firing initiation and regulates catecholamine secretion in MCCs. Nav channel inactivation becomes important during periods of high activity, mimicking stress responses.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jphysiol.2014.283374","type":"journal-article","created":{"date-parts":[[2014,12,12]],"date-time":"2014-12-12T11:58:29Z","timestamp":1418385509000},"page":"905-927","source":"Crossref","is-referenced-by-count":61,"title":["Reduced availability of voltage\u2010gated sodium channels by depolarization or blockade by tetrodotoxin boosts burst firing and catecholamine release in mouse chromaffin cells"],"prefix":"10.1113","volume":"593","author":[{"given":"David H. F.","family":"Vandael","sequence":"first","affiliation":[{"name":"Department of Drug Science Laboratory of Cellular and Molecular Neuroscience NIS Center, CNISM Unit Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo M.","family":"Ottaviani","sequence":"additional","affiliation":[{"name":"Department of Drug Science Laboratory of Cellular and Molecular Neuroscience NIS Center, CNISM Unit Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Legros","sequence":"additional","affiliation":[{"name":"CNRS UMR6214 Inserm U1083 Laboratory of Integrated Neurovascular and mitochondrial Biology Angers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudie","family":"Lefort","sequence":"additional","affiliation":[{"name":"CNRS UMR6214 Inserm U1083 Laboratory of Integrated Neurovascular and mitochondrial Biology Angers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie C.","family":"Gu\u00e9rineau","sequence":"additional","affiliation":[{"name":"CNRS UMR6214 Inserm U1083 Laboratory of Integrated Neurovascular and mitochondrial Biology Angers France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Allio","sequence":"additional","affiliation":[{"name":"Department of Drug Science Laboratory of Cellular and Molecular Neuroscience NIS Center, CNISM Unit Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Carabelli","sequence":"additional","affiliation":[{"name":"Department of Drug Science Laboratory of Cellular and Molecular Neuroscience NIS Center, CNISM Unit Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Carbone","sequence":"additional","affiliation":[{"name":"Department of Drug Science Laboratory of Cellular and Molecular Neuroscience NIS Center, CNISM Unit Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,26]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1254\/jjp.61.145"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005633107"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2148"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5443-12.2013"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1976.sp011618"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1976.sp011638"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/35077553"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2002.017749"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(03)74567-6"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.0073g.x"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00249-007-0138-2"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.132274"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00254208"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1987.sp016552"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00531-2"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.12.011"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.57.4.4"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-01-00073.2003"},{"key":"e_1_2_6_20_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/j.0954-6820.1983.tb01622.x","article-title":"Adrenergic control of Na+\u2010K+\u2010homoeostasis","volume":"672","author":"Clausen T (","year":"1983","journal-title":"Acta Med Scand Suppl"},{"key":"e_1_2_6_21_1","doi-asserted-by":"crossref","first-page":"887","DOI":"10.4269\/ajtmh.2008.79.887","article-title":"Estimation of copy number using SYBR Green: confounding by AT\u2010rich DNA and by variation in amplicon length","volume":"79","author":"Colborn JM","year":"2008","journal-title":"Am J Trop Med Hyg"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-16-05952.2001"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2007.01807.x"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3938"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-35-11235.2003"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.12.048"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00292.2007"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1982.sp014394"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.95.6.1139"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00039.2005"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(88)90307-7"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-012-9707-7"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2008.05521.x"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1980.sp013431"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1995.tb07091.x"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/348545a0"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1709-07.2007"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/j..2003.t01-1-00191.x"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2000.00871.x"},{"key":"e_1_2_6_40_1","doi-asserted-by":"crossref","first-page":"7334","DOI":"10.1523\/JNEUROSCI.19-17-07334.1999","article-title":"High conductance sustained single\u2010channel activity responsible for the low\u2010threshold persistent Na(+) current in entorhinal cortex neurons","volume":"19","author":"Magistretti J","year":"1999","journal-title":"J Neurosci"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.4161\/chan.5.3.15271"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2007.04.015"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2007.01815.x"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-008-0584-4"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4961-09.2010"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-15-05397.2001"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201411253"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3430-07.2007"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21484"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1988.254.5.C675"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1186\/1744-8069-2-33"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404915101"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2007.01816.x"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-12-04517.1997"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1979.sp012636"},{"key":"e_1_2_6_56_1","first-page":"365","article-title":"Primer3 on the WWW for general users and for biologist programmers","volume":"132","author":"Rozen S","year":"2000","journal-title":"Methods Mol Biol"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2005.083089"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.23.14805"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-0270(00)00309-5"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-16-06093.1998"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-29-09650.2003"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00574-3"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.4.1527"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1251-12.2012"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-010-8151-3"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3715-12.2012"},{"key":"e_1_2_6_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1748-1716.2007.01810.x"},{"key":"e_1_2_6_68_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1981.sp013676"},{"key":"e_1_2_6_69_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2001.013370"},{"key":"e_1_2_6_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2011.07.029"},{"key":"e_1_2_6_71_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.8.3498"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1113%2Fjphysiol.2014.283374","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/jphysiol.2014.283374","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T21:06:27Z","timestamp":1717621587000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/jphysiol.2014.283374"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,26]]},"references-count":70,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2015,2,15]]}},"alternative-id":["10.1113\/jphysiol.2014.283374"],"URL":"https:\/\/doi.org\/10.1113\/jphysiol.2014.283374","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,26]]}}}