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At low pH<jats:sub>o<\/jats:sub>, they depolarize, undergo burst\u2010firing and increase catecholamine\u2010secretion, generating an effective physiological response that may compensate for the acute acidosis and hyperkalaemia generated during heavy exercise and muscle fatigue.<\/jats:p><\/jats:list-item><\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Mouse chromaffin cells (MCCs) generate action potential (AP) firing that regulates the Ca<jats:sup>2+<\/jats:sup>\u2010dependent release of catecholamines (CAs). Recent findings indicate that MCCs possess a variety of spontaneous firing modes that span from the common \u2018tonic\u2010irregular\u2019 to the less frequent \u2018burst\u2019 firing. This latter is evident in a small fraction of MCCs but occurs regularly when Nav1.3\/1.7 channels are made less available or when the Slo1\u03b22\u2010subunit responsible for BK channel inactivation is deleted. Burst firing causes large increases of Ca<jats:sup>2+<\/jats:sup>\u2010entry and potentiates CA release by \u223c3.5\u2010fold and thus may be a key mechanism for regulating MCC function. With the aim to uncover a physiological role for burst\u2010firing we investigated the effects of acidosis on MCC activity. Lowering the extracellular pH (pH<jats:sub>o<\/jats:sub>) from 7.4 to 7.0 and 6.6 induces cell depolarizations of 10\u201315\u00a0mV that generate repeated bursts. Bursts at pH<jats:sub>o<\/jats:sub>6.6 lasted \u223c330\u00a0ms, occurred at 1\u20132\u00a0Hz and caused an \u223c7\u2010fold increase of CA cumulative release. Burst firing originates from the inhibition of the pH\u2010sensitive TASK\u20101\/TASK\u20103 channels and from a 40% BK channel conductance reduction at pH<jats:sub>o<\/jats:sub>7.0. The same pH<jats:sub>o<\/jats:sub>had little or no effect on Nav, Cav, Kv and SK channels that support AP firing in MCCs. Burst firing of pH<jats:sub>o<\/jats:sub>6.6 could be mimicked by mixtures of the TASK\u20101 blocker A1899 (300\u00a0n<jats:sc>m<\/jats:sc>) and BK blocker paxilline (300\u00a0n<jats:sc>m<\/jats:sc>) and could be prevented by blocking L\u2010type channels by adding 3\u00a0\u03bc<jats:sc>m<\/jats:sc>nifedipine. Mixtures of the two blockers raised cumulative CA\u2010secretion even more than low pH<jats:sub>o<\/jats:sub>(\u223c12\u2010fold), showing that the action of protons on vesicle release is mainly a result of the ionic conductance changes that increase Ca<jats:sup>2+<\/jats:sup>\u2010entry during bursts. Our data provide direct evidence suggesting that MCCs respond to low pH<jats:sub>o<\/jats:sub>with sustained depolarization, burst firing and enhanced CA\u2010secretion, thus mimicking the physiological response of CCs to acute acidosis and hyperkalaemia generated during heavy exercise and muscle fatigue.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp273735","type":"journal-article","created":{"date-parts":[[2016,12,27]],"date-time":"2016-12-27T10:53:06Z","timestamp":1482835986000},"page":"2587-2609","source":"Crossref","is-referenced-by-count":37,"title":["Low pH<sub>o<\/sub>boosts burst firing and catecholamine release by blocking TASK\u20101 and BK channels while preserving Cav1 channels in mouse chromaffin cells"],"prefix":"10.1113","volume":"595","author":[{"given":"Laura","family":"Guarina","sequence":"first","affiliation":[{"name":"Department of Drug Science, Laboratory of Cellular and Molecular Neuroscience, NIS Centre CNISM Unit Torino Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H. 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